- Email: [email protected]
The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before
Structure
Previews The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before Sansana Sawasdikosol1,* and Steven Burakoff1 1Tisch Cancer Institute, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, 1470 Madison Avenue, Rm. S5-107, New York, NY 10029, USA *Correspondence: [email protected] https://doi.org/10.1016/j.str.2018.12.009
In this issue of Structure, Wu et al. (2018) report several apo and small-molecule inhibitor-bound structures of the kinase domain of hematopoietic progenitor kinase 1, a ser/thr kinase that functions as an inhibitor of T cell activation. The studies reveal that the HPK1 kinase domain exists as a domain-swapped dimer. Despite having been trained to avoid recognizing self-antigens by central and peripheral tolerance mechanisms, T cells can recognize minor antigen differences that exist in cancer cells in the form of mutated or aberrantly expressed proteins. T cells that recognize these tumorassociated neo-antigens would then engage in cytolytic killing of these cancer cells. However, T cells that have to maintain their vigilant fight against cancer cells eventually become ‘‘exhausted’’ and cannot continue to productively engage and kill cancer cells (Wherry and Kurachi, 2015). Immune checkpoint receptors such as PD-1, TIM-3, and LAG3 are biomarkers of exhausted T cells and function as part of the negative feedback mechanisms that maintain T cells in an exhausted, non-responsive state. Therefore, using antagonistic antibodies that interfere with the function of these inhibitory receptors has proven to be a clinically effective approach to reinvigorate the anti-tumor potential of exhausted T cells. The demonstrated success of using antibodies as immune checkpoint inhibitor drugs for the treatment of aggressive malignancies had provided a solid proof of principle that this therapeutic approach works (Ribas and Wolchok, 2018). Thus, accelerated efforts are being made to further identify new immune checkpoint receptor antibodies and to develop them as novel immune checkpoint drugs to expand the repertoire of immuno-oncologic therapeutics. While these efforts are likely to produce new immune checkpoint drugs, the approach doesn’t allow targeting of numerous
cytosolic negative regulators of T cell activation. A large number of well-characterized negative feedback pathways, including the hematopoietic progenitor kinase 1 (HPK1)-regulated pathways, are activated shortly after the T cell receptor is engaged so that they can modulate the strength and duration of TCR-generated activation signals. While these cytosolic negative regulatory pathways are enticing targets for immune-modulation therapy, their functions cannot be manipulated through the use of inhibitory antibodies. Thus, the thrust of a second wave of immunooncologic research is focused on identifying suitable intracellular targets whose inhibitory functions are amenable to manipulations by cell-permeable smallmolecule compounds. Inhibitory kinases, phosphatases, ubiquitin ligases, and transcription factors are just a few of the known classes of enzymes and transcription factors that play critical roles in limiting T cell activation (Adams et al., 2015). However, among the class of molecules mentioned above, only kinases have decades of a proven track record as ‘‘druggable’’ targets. In many ways, identifying validated kinases to target for inhibition is one of the biggest hurdles in the drug development process. Once the inhibitory target of T cell activation is identified, the development of small molecule inhibitor remains a serious challenge. Unlike small molecule kinase inhibitors targeting molecular drivers of cancer growth, inhibitors of negative regulatory kinases involved in T cell activation must inhibit only the kinase activity of the intended
target while sparing the kinase activities of all kinases that are required for robust T cell activation. This level of exquisite specificity is a demanding bar to clear and selecting the kinase targets that can meet this requirement is of paramount importance. Structures of HPK1 revealed by Wang and colleagues represent one of the critical initial steps necessary to facilitate the development of exquisitely specific small-molecule-based immune response modulators of HPK1 that are capable of augmenting anti-tumor immunity (Wu et al., 2018). There are many compelling reasons why Wu et al. chose to determine the structures of this important hematopoietic cell-restricted kinase. HPK1 is a member of the GCK-I sub-family of Ste-20 serine/threonine kinases. Its catalytic activity is activated in response to TCR engagement and had been shown through ectopic expression studies to be a negative regulator of Erk MAPK and AP-1-regulated gene transcription (Liou et al., 2000). Genetic studies had revealed that targeted disruption of HPK1 alleles confer HPK1-deficient T cells (Alzabin et al., 2010; Shui et al., 2007) and bone marrow-derived dendritic cells (BMDC) (Alzabin et al., 2009) with enhanced immune functions. The absence of HPK1 in BMDC confers them with elevated co-receptor molecule expression (CD80, CD86, and MHCII I-Ab) when stimulated with LPS and an enhanced antigen-presenting ability that coincides with the ability to elicit an increased anti-tumor immune response when used as a dendritic cell vaccine (Alzabin et al., 2009) (Figure 1). Equally
Structure 27, January 2, 2019 ª 2018 Published by Elsevier Ltd. 1
Structure
Previews
Figure 1. A Schematic Depicting How the Loss of HPK1 or Inhibition of HPK1 Kinase Activity May Have on Anti-tumor Immunity Treatment of tumor-bearing mice or cancer patients with small-molecule inhibitor of HPK1might elicit enhanced tumor immunity similar to those observed in HPK1-deficient (HPK1 / ) mouse or in mice with catalytically inactive HPK1 alleles.
importantly, through adoptive T cell transfer into T cell-deficient RAG2 / mice, it has been shown that HPK1 / mice possess robust T cell-mediated anti-tumor immunity in a Lewis lung carcinoma syngeneic murine tumor model (Alzabin et al., 2010) (Figure 1). Recently, using mice engineered to carry a catalytically inactivating point mutation at residue 46 of HPK1 from lysine to glutamic acid, the enhanced anti-tumor immune response observed to MC38, a syngeneic murine model of adenocarcinoma, has implicated the kinase activity of HPK1 as the key driver of the inhibition of T cells (Hernandez et al., 2018). The study also revealed that the enhanced anti-tumor activity could be further augmented by concurrent administration of anti-PD-1 antibody therapy, suggesting that the two inhibitory pathways are non-overlapping and thus could be used concurrently as dual therapy that might enhance the anti-tumor immune response additively or synergistically (Hernandez et al., 2018) (Figure 1). Taken together, these findings support previous speculation that HPK1 might be an ideal 2 Structure 27, January 2, 2019
target for small-molecule-mediated inhibition that would provoke an enhanced anti-tumor immunity (Sawasdikosol et al., 2012). The HPK1 structures solved by the Wang group (Wu et al., 2018) provide a number of interesting insights into the structural characteristics of the HPK1 kinase domain in several conformational states. While possessing the overall conserved bilobed structure of a typical kinase domain, two distinctive features were observed in all HPK1 variants reported in this study: the presence of a three-turn a-helical structure at the N terminus of the activation segment (AS) and the existence of HPK1 as a ‘‘face-toface’’ domain-swapped dimer in the crystallographic state as well as in solution. The three-turn a-helical structure is thought to confer structural rigidity to the AS that usually exists as an extended loop in most kinases. In the extended loop conformation, the AS is amenable to phosphorylation-dependent conformational changes required for activation via cis or trans phosphorylation of regulatory residues. Despite possessing the
a-helical structure at the N terminus of the AS, the structure of the phosphomimetic HPK1 mutant (Thr165Glu/ Ser171Glu, TSEE) possesses characteristics reminiscent of a competent kinase domain—catalytic lysine at residue 46 hydrogen-bonded with the a-phosphate and salt-bridged with aC-helix while the regulatory spine residues are situated in a ‘‘kinase-active’’ conformation. This finding suggests that the a-helical structure does not interfere with phosphorylation-dependent regulation of HPK1 kinase activity. Conversely, the presence of an a-helical structure was not sufficient to confer catalytic activity to the phospho-deficient HPK1 mutant that lacks the phosphate acceptable side chain at serine 171 (Ser171Ala, SA). HPK1 structures also revealed the existing relationship between the AS and the domain-swapped dimers. In all the structures determined, a large portion of AS participates in the approximately 5000 A˚2 of buried surface area formed between the two face-to-face HPK1 protomers. The dimer is situated in such a way that the aEF helix of one HPK1 protomer interacts with the region formed by the aF and aG of the other protomer. It is interesting to speculate that the domain-swapped dimerization of HPK1 protein may confer it with an additional layer of regulatory mechanism that might control substrate selectivity and/or the cis or trans phosphorylating activity. It is interesting to note that 5 of the 7 domain-swapped structures reported to date are members of the Ste20 family of serine/threonine kinases. This relative prevalence of a domain-swapped configuration might offer a selective advantage in designing a small molecule inhibitor that can leverage the relatively unique structural feature of this kinase domain. Every explorer knows that a journey into the unknown will be made much easier if there is a detailed road map available to consult. Wu et al. had provided medicinal chemists with several detailed structural insights regarding the HPK1 kinase domain. These structures will facilitate the structure-activity relationship optimization and will enable researchers to improve upon the GNE-1858 HPK1 inhibitor or other inhibitors that may emerge from the future screening of small-molecule libraries.
Structure
Previews ACKNOWLEDGMENTS We apologize to colleagues who have contributed valuable work toward the understanding of HPK1 but were not cited due to space limitations. REFERENCES Adams, J.L., Smothers, J., Srinivasan, R., and Hoos, A. (2015). Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov. 14, 603–622. Alzabin, S., Bhardwaj, N., Kiefer, F., Sawasdikosol, S., and Burakoff, S. (2009). Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J. Immunol. 182, 6187–6194. Alzabin, S., Pyarajan, S., Yee, H., Kiefer, F., Suzuki, A., Burakoff, S., and Sawasdikosol, S. (2010).
Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunol. Immunother. 59, 419–429. Hernandez, S., Qing, J., Thibodeau, R.H., Du, X., Park, S., Lee, H.M., Xu, M., Oh, S., Navarro, A., Roose-Girma, M., et al. (2018). The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep. 25, 80–94. Liou, J., Kiefer, F., Dang, A., Hashimoto, A., Cobb, M.H., Kurosaki, T., and Weiss, A. (2000). HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1. Immunity 12, 399–408. Ribas, A., and Wolchok, J.D. (2018). Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355.
Sawasdikosol, S., Zha, R., Yang, B., and Burakoff, S. (2012). HPK1 as a novel target for cancer immunotherapy. Immunol. Res. 54, 262–265. Shui, J.W., Boomer, J.S., Han, J., Xu, J., Dement, G.A., Zhou, G., and Tan, T.H. (2007). Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cellmediated immune responses. Nat. Immunol. 8, 84–91. Wherry, E.J., and Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499. Wu, P., Sneeringer, C.J., Pitts, K.E., Day, E.S., Chan, B.K., Wei, B., Lehoux, I., Mortara, K., Li, H., Wu, J., et al. (2018). Hematopoietic progenitor kinase-1 structure in a domain-swapped dimer. Structure 27, this issue, 125–133.
Drebrin-Homer Interaction at An Atomic Scale Yasunori Hayashi1,* 1Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.str.2018.12.008
In this issue of Structure, Li et al. (2018) describe a crystallographic view of the Drebrin-Homer interaction, mediated by the Homer binding motif of Drebrin and EVH1 domain of Homer. This interaction enables cross-linking of monomeric Drebrin by tetrameric Homer, which is required for efficient F-actin bundling. Drebrin is a protein identified as develop- Overexpression of Drebrin elongates the in non-neuronal cells generates promentally regulated brain protein (Shirao spines while a knock-down slows synap- trusions that contain F-actin similar to and Obata, 1985; Koganezawa et al., tic maturation and protein accumulation. the dendritic spine. In the knock-out ani2017 for review). It has an N-terminal Interestingly, overexpression of Drebrin mals, synaptic plasticity and learning caactin-depolymerizing factor pacity are impaired. Therefore, homology (ADF-H) domain, a Drebrin is crucial for normal coiled-coil (CC) domain, and brain function. a carboxyl-tail that comprises The proteins that interact nearly half of the protein but with Drebrin are key to its does not have any known profunction. Drebrin interacts tein domain and is possibly with F-actin through the CC unstructured (Figure 1). As domain (Figure 1), but not development progresses, the through the ADF-H domain, embryonic Drebrin E form is even though it has homology replaced with the adult Drewith ADF, an actin side-bindbrin A form generated by ing protein. Instead, the alternative splicing. Drebrin is ADF-H domain interacts with Figure 1. Domain Structure, Phosphorylation, and Protein expressed both in neuronal ZMYND8, a histone marker Interaction of Drebrin and non-neuronal tissues. In reader. Drebrin also interacts ADF-H, actin depolymerizing factor-homology; CC, coiled-coil; Ins, Drebrin A mature neuronal tissue, it is with the EVH1 domain of Homspecific insert; PRD, proline-rich domain; HBM, Homer-binding motif; P, phosphorylation sites; and EVH, ena-vasp homology. While two HBMs have predominantly expressed in er, a postsynaptic scaffolding been suggested, a new work by Li et al. (2018) confirmed that only the aminothe dendrites and is especially protein, through PPxxF motifs terminal one is functional. Serine 142 phosphorylation mentioned in the text enriched in spines that harbor in the carboxyl tail. To fully is highlighted in red. Phosphorylation sites are obtained from mouse Drebrin in UniProt (Q9QXS6). the excitatory synapses. understand the functional Structure 27, January 2, 2019 ª 2018 Elsevier Ltd. 3
Previews The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before Sansana Sawasdikosol1,* and Steven Burakoff1 1Tisch Cancer Institute, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, 1470 Madison Avenue, Rm. S5-107, New York, NY 10029, USA *Correspondence: [email protected] https://doi.org/10.1016/j.str.2018.12.009
In this issue of Structure, Wu et al. (2018) report several apo and small-molecule inhibitor-bound structures of the kinase domain of hematopoietic progenitor kinase 1, a ser/thr kinase that functions as an inhibitor of T cell activation. The studies reveal that the HPK1 kinase domain exists as a domain-swapped dimer. Despite having been trained to avoid recognizing self-antigens by central and peripheral tolerance mechanisms, T cells can recognize minor antigen differences that exist in cancer cells in the form of mutated or aberrantly expressed proteins. T cells that recognize these tumorassociated neo-antigens would then engage in cytolytic killing of these cancer cells. However, T cells that have to maintain their vigilant fight against cancer cells eventually become ‘‘exhausted’’ and cannot continue to productively engage and kill cancer cells (Wherry and Kurachi, 2015). Immune checkpoint receptors such as PD-1, TIM-3, and LAG3 are biomarkers of exhausted T cells and function as part of the negative feedback mechanisms that maintain T cells in an exhausted, non-responsive state. Therefore, using antagonistic antibodies that interfere with the function of these inhibitory receptors has proven to be a clinically effective approach to reinvigorate the anti-tumor potential of exhausted T cells. The demonstrated success of using antibodies as immune checkpoint inhibitor drugs for the treatment of aggressive malignancies had provided a solid proof of principle that this therapeutic approach works (Ribas and Wolchok, 2018). Thus, accelerated efforts are being made to further identify new immune checkpoint receptor antibodies and to develop them as novel immune checkpoint drugs to expand the repertoire of immuno-oncologic therapeutics. While these efforts are likely to produce new immune checkpoint drugs, the approach doesn’t allow targeting of numerous
cytosolic negative regulators of T cell activation. A large number of well-characterized negative feedback pathways, including the hematopoietic progenitor kinase 1 (HPK1)-regulated pathways, are activated shortly after the T cell receptor is engaged so that they can modulate the strength and duration of TCR-generated activation signals. While these cytosolic negative regulatory pathways are enticing targets for immune-modulation therapy, their functions cannot be manipulated through the use of inhibitory antibodies. Thus, the thrust of a second wave of immunooncologic research is focused on identifying suitable intracellular targets whose inhibitory functions are amenable to manipulations by cell-permeable smallmolecule compounds. Inhibitory kinases, phosphatases, ubiquitin ligases, and transcription factors are just a few of the known classes of enzymes and transcription factors that play critical roles in limiting T cell activation (Adams et al., 2015). However, among the class of molecules mentioned above, only kinases have decades of a proven track record as ‘‘druggable’’ targets. In many ways, identifying validated kinases to target for inhibition is one of the biggest hurdles in the drug development process. Once the inhibitory target of T cell activation is identified, the development of small molecule inhibitor remains a serious challenge. Unlike small molecule kinase inhibitors targeting molecular drivers of cancer growth, inhibitors of negative regulatory kinases involved in T cell activation must inhibit only the kinase activity of the intended
target while sparing the kinase activities of all kinases that are required for robust T cell activation. This level of exquisite specificity is a demanding bar to clear and selecting the kinase targets that can meet this requirement is of paramount importance. Structures of HPK1 revealed by Wang and colleagues represent one of the critical initial steps necessary to facilitate the development of exquisitely specific small-molecule-based immune response modulators of HPK1 that are capable of augmenting anti-tumor immunity (Wu et al., 2018). There are many compelling reasons why Wu et al. chose to determine the structures of this important hematopoietic cell-restricted kinase. HPK1 is a member of the GCK-I sub-family of Ste-20 serine/threonine kinases. Its catalytic activity is activated in response to TCR engagement and had been shown through ectopic expression studies to be a negative regulator of Erk MAPK and AP-1-regulated gene transcription (Liou et al., 2000). Genetic studies had revealed that targeted disruption of HPK1 alleles confer HPK1-deficient T cells (Alzabin et al., 2010; Shui et al., 2007) and bone marrow-derived dendritic cells (BMDC) (Alzabin et al., 2009) with enhanced immune functions. The absence of HPK1 in BMDC confers them with elevated co-receptor molecule expression (CD80, CD86, and MHCII I-Ab) when stimulated with LPS and an enhanced antigen-presenting ability that coincides with the ability to elicit an increased anti-tumor immune response when used as a dendritic cell vaccine (Alzabin et al., 2009) (Figure 1). Equally
Structure 27, January 2, 2019 ª 2018 Published by Elsevier Ltd. 1
Structure
Previews
Figure 1. A Schematic Depicting How the Loss of HPK1 or Inhibition of HPK1 Kinase Activity May Have on Anti-tumor Immunity Treatment of tumor-bearing mice or cancer patients with small-molecule inhibitor of HPK1might elicit enhanced tumor immunity similar to those observed in HPK1-deficient (HPK1 / ) mouse or in mice with catalytically inactive HPK1 alleles.
importantly, through adoptive T cell transfer into T cell-deficient RAG2 / mice, it has been shown that HPK1 / mice possess robust T cell-mediated anti-tumor immunity in a Lewis lung carcinoma syngeneic murine tumor model (Alzabin et al., 2010) (Figure 1). Recently, using mice engineered to carry a catalytically inactivating point mutation at residue 46 of HPK1 from lysine to glutamic acid, the enhanced anti-tumor immune response observed to MC38, a syngeneic murine model of adenocarcinoma, has implicated the kinase activity of HPK1 as the key driver of the inhibition of T cells (Hernandez et al., 2018). The study also revealed that the enhanced anti-tumor activity could be further augmented by concurrent administration of anti-PD-1 antibody therapy, suggesting that the two inhibitory pathways are non-overlapping and thus could be used concurrently as dual therapy that might enhance the anti-tumor immune response additively or synergistically (Hernandez et al., 2018) (Figure 1). Taken together, these findings support previous speculation that HPK1 might be an ideal 2 Structure 27, January 2, 2019
target for small-molecule-mediated inhibition that would provoke an enhanced anti-tumor immunity (Sawasdikosol et al., 2012). The HPK1 structures solved by the Wang group (Wu et al., 2018) provide a number of interesting insights into the structural characteristics of the HPK1 kinase domain in several conformational states. While possessing the overall conserved bilobed structure of a typical kinase domain, two distinctive features were observed in all HPK1 variants reported in this study: the presence of a three-turn a-helical structure at the N terminus of the activation segment (AS) and the existence of HPK1 as a ‘‘face-toface’’ domain-swapped dimer in the crystallographic state as well as in solution. The three-turn a-helical structure is thought to confer structural rigidity to the AS that usually exists as an extended loop in most kinases. In the extended loop conformation, the AS is amenable to phosphorylation-dependent conformational changes required for activation via cis or trans phosphorylation of regulatory residues. Despite possessing the
a-helical structure at the N terminus of the AS, the structure of the phosphomimetic HPK1 mutant (Thr165Glu/ Ser171Glu, TSEE) possesses characteristics reminiscent of a competent kinase domain—catalytic lysine at residue 46 hydrogen-bonded with the a-phosphate and salt-bridged with aC-helix while the regulatory spine residues are situated in a ‘‘kinase-active’’ conformation. This finding suggests that the a-helical structure does not interfere with phosphorylation-dependent regulation of HPK1 kinase activity. Conversely, the presence of an a-helical structure was not sufficient to confer catalytic activity to the phospho-deficient HPK1 mutant that lacks the phosphate acceptable side chain at serine 171 (Ser171Ala, SA). HPK1 structures also revealed the existing relationship between the AS and the domain-swapped dimers. In all the structures determined, a large portion of AS participates in the approximately 5000 A˚2 of buried surface area formed between the two face-to-face HPK1 protomers. The dimer is situated in such a way that the aEF helix of one HPK1 protomer interacts with the region formed by the aF and aG of the other protomer. It is interesting to speculate that the domain-swapped dimerization of HPK1 protein may confer it with an additional layer of regulatory mechanism that might control substrate selectivity and/or the cis or trans phosphorylating activity. It is interesting to note that 5 of the 7 domain-swapped structures reported to date are members of the Ste20 family of serine/threonine kinases. This relative prevalence of a domain-swapped configuration might offer a selective advantage in designing a small molecule inhibitor that can leverage the relatively unique structural feature of this kinase domain. Every explorer knows that a journey into the unknown will be made much easier if there is a detailed road map available to consult. Wu et al. had provided medicinal chemists with several detailed structural insights regarding the HPK1 kinase domain. These structures will facilitate the structure-activity relationship optimization and will enable researchers to improve upon the GNE-1858 HPK1 inhibitor or other inhibitors that may emerge from the future screening of small-molecule libraries.
Structure
Previews ACKNOWLEDGMENTS We apologize to colleagues who have contributed valuable work toward the understanding of HPK1 but were not cited due to space limitations. REFERENCES Adams, J.L., Smothers, J., Srinivasan, R., and Hoos, A. (2015). Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov. 14, 603–622. Alzabin, S., Bhardwaj, N., Kiefer, F., Sawasdikosol, S., and Burakoff, S. (2009). Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J. Immunol. 182, 6187–6194. Alzabin, S., Pyarajan, S., Yee, H., Kiefer, F., Suzuki, A., Burakoff, S., and Sawasdikosol, S. (2010).
Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunol. Immunother. 59, 419–429. Hernandez, S., Qing, J., Thibodeau, R.H., Du, X., Park, S., Lee, H.M., Xu, M., Oh, S., Navarro, A., Roose-Girma, M., et al. (2018). The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep. 25, 80–94. Liou, J., Kiefer, F., Dang, A., Hashimoto, A., Cobb, M.H., Kurosaki, T., and Weiss, A. (2000). HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1. Immunity 12, 399–408. Ribas, A., and Wolchok, J.D. (2018). Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355.
Sawasdikosol, S., Zha, R., Yang, B., and Burakoff, S. (2012). HPK1 as a novel target for cancer immunotherapy. Immunol. Res. 54, 262–265. Shui, J.W., Boomer, J.S., Han, J., Xu, J., Dement, G.A., Zhou, G., and Tan, T.H. (2007). Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cellmediated immune responses. Nat. Immunol. 8, 84–91. Wherry, E.J., and Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499. Wu, P., Sneeringer, C.J., Pitts, K.E., Day, E.S., Chan, B.K., Wei, B., Lehoux, I., Mortara, K., Li, H., Wu, J., et al. (2018). Hematopoietic progenitor kinase-1 structure in a domain-swapped dimer. Structure 27, this issue, 125–133.
Drebrin-Homer Interaction at An Atomic Scale Yasunori Hayashi1,* 1Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.str.2018.12.008
In this issue of Structure, Li et al. (2018) describe a crystallographic view of the Drebrin-Homer interaction, mediated by the Homer binding motif of Drebrin and EVH1 domain of Homer. This interaction enables cross-linking of monomeric Drebrin by tetrameric Homer, which is required for efficient F-actin bundling. Drebrin is a protein identified as develop- Overexpression of Drebrin elongates the in non-neuronal cells generates promentally regulated brain protein (Shirao spines while a knock-down slows synap- trusions that contain F-actin similar to and Obata, 1985; Koganezawa et al., tic maturation and protein accumulation. the dendritic spine. In the knock-out ani2017 for review). It has an N-terminal Interestingly, overexpression of Drebrin mals, synaptic plasticity and learning caactin-depolymerizing factor pacity are impaired. Therefore, homology (ADF-H) domain, a Drebrin is crucial for normal coiled-coil (CC) domain, and brain function. a carboxyl-tail that comprises The proteins that interact nearly half of the protein but with Drebrin are key to its does not have any known profunction. Drebrin interacts tein domain and is possibly with F-actin through the CC unstructured (Figure 1). As domain (Figure 1), but not development progresses, the through the ADF-H domain, embryonic Drebrin E form is even though it has homology replaced with the adult Drewith ADF, an actin side-bindbrin A form generated by ing protein. Instead, the alternative splicing. Drebrin is ADF-H domain interacts with Figure 1. Domain Structure, Phosphorylation, and Protein expressed both in neuronal ZMYND8, a histone marker Interaction of Drebrin and non-neuronal tissues. In reader. Drebrin also interacts ADF-H, actin depolymerizing factor-homology; CC, coiled-coil; Ins, Drebrin A mature neuronal tissue, it is with the EVH1 domain of Homspecific insert; PRD, proline-rich domain; HBM, Homer-binding motif; P, phosphorylation sites; and EVH, ena-vasp homology. While two HBMs have predominantly expressed in er, a postsynaptic scaffolding been suggested, a new work by Li et al. (2018) confirmed that only the aminothe dendrites and is especially protein, through PPxxF motifs terminal one is functional. Serine 142 phosphorylation mentioned in the text enriched in spines that harbor in the carboxyl tail. To fully is highlighted in red. Phosphorylation sites are obtained from mouse Drebrin in UniProt (Q9QXS6). the excitatory synapses. understand the functional Structure 27, January 2, 2019 ª 2018 Elsevier Ltd. 3