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New functional polymorphism in psoriasis
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M u c h progress on the protein-folding problem The native conformation of a protein is implicit in its primary sequence, but to predict that conformationis no easy task. Now, George D. Rose and his colleague, Rajgopal Srinivasan, (Johns Hopkins University, Baltimore, MD, USA) have developed a remarkably successful algorithm for predictingthe folding pattem of monomeric,soluble globular proteins [Srinivasan, R. and Rose, G.D. (1995) Proteht Struct. Funct. Genet. 22, 81-99]. The program, dubbed LINUS (for Local Independently Nucleated Units of Structure), in honor of the late Linus Pauling, requires several days of calculationson a UnixrM-basedworkstation to predict the structure of a protein of 100 residues. The results on test proteins are comparable in quality to a low-resolution determination of structure by X-ray crystallography, which would typically require several months to do. LINUS proceeds repeatedly through the polypeptidechain from the N- to the C terminus, generating random conformations by perturbing the bond angles in groups of three adjacent residues at a time. Each new conformation is compared with the previous one, and accepted or
rejected on the basis of a highly simplified energy function, which includes hard-sphererepulsion(the 'bump check'), hydrogenbonding and the tendency for hydrophobic side chains to be buried inside the molecule. Conformations of greater than minimum energy are sometimes accepted, using a Monte Carlo procedure, in order to bounce the structure out of local energy minima. The structures of the amino acid side chains are simplified; for example, phenylalanine,tryptophan and tyrosine are all approximated by the same side chain consisting of just two pseudo-atoms. At first, the interaction interval, or distance over which residues can 'feel' each other, is limited to six residues. After 5000 cycles through the sequence with an interaction interval of six, the conformations generated are classified as helix, sheet, turn or loop. Any chain segment that assumes a single structure at least 70% of the time is frozen in that configuration, after which the interaction interval is increased to 12 and the chain-perturbation process is repeated. Any chain segment that adopts a given conformation in 70% of the trials at a given interactionintervalis frozen
disease characterized by a rash and, in more severe forms, it may also involve nail dystrophy and inflammatory arthritis. Associated psychological problems can have a very adverse effect on patients' quality of life. Despite the great efforts that have been made to understand the nature of this disease, it is surprising that we still know so little. There are no good animal models, and drug development has largely been a 'hit-or-miss' affair. The most promising recent advance has been the introduction of vitamin D analogues, particularly calcipotriol. Mike Cork, Franco di Giovine and Gordon Duff (Dermatology and Molecular Medicine Sections of the Department of Medicine and Pharmacology, University of Sheffield, UK), have been studying the molecular basis of psoriasis in the hope that this will be the best way to discover an effective treatment. At the recent annual meeting of the British Association of Dermatologists*, Cork described their discovery of a functional
with psoriasis. Earlier, the group had found an association between a polymorphism in the IL-1 receptor antagonist gene (IL-1RA) and psoriasis and turned their attention to another polymorphism in exon 5 of the IL-1 [3gene. They have screened a normal population of 198 subjects using PCR and restriction enzyme analysis and found that the frequency of the rare allele is0.17. They have also studied the polymorphism through three generations of a family and found that it follows normal Mendelian segregation. The rare allele of this polymorphism was associated with high production of IL-1[3 protein. They have now investigated a group of 180 patients with psoriasis attending a local out-patient clinic and found a higher frequency of the rarer allele of 0.30, with carriage increased from 0.33 to *Annual meeting of the British Association of Dermatologists, Glasgow, UK, 4--8 July 1995.
in place.After each set of 5000 trials, the interaction interval is increased by six, until it encompasses the entire protein. The entire process is called 'folding by hierarchic condensation'. Implicit in the procedure are assumptions that highly stable interactionsbetween nearby residues are more important than long-range interaction, that the precise structure of side chains is not essential to the overall folding pattern, and that the native conformations are robust and overdetermined, rather than, as others have surmised, precarionsly poised. Rose and Srinivasan have not adapted their program to membrane proteins; there would be few known structures with which to check the results. Nor are they soliciting protein sequences to test. They are refining the program, hoping to make it run faster and on less-powerfulcomputers, so others will be able to use it to esthnate folding patterns for the thousands of protein sequences now pouring into databases, thereby providing clues about their function. Paul M. Rowe
individuals in the under-30-yearsold grgup had a higher frequencyof the rarer allele (0:34) compared with those in the over-40-years old group (0.27). This is the first report of a genetic association with psoriasis in which function has been demonstrated, and it reinforces the current hypothesis that IL-1 genes play a significant role in the pathogenesis of the disease. According to Cork, increased cytokine levels lead to more inflammation, which is the major characteristic of the condition. The new vitamin D analogues antagonize the actions of IL-I and it may be that these genes confer a susceptibility to developing psoriasis, and thus their characterization may help identify at-risk individuals..In Cork's opinion: 'understanding the genetic component of polymorphism will lead to the development of more specific therapies'. Let's hope he is right. David B. Jack m
©1995, Elsevier Science Ltd
257
N
e
w
s
M u c h progress on the protein-folding problem The native conformation of a protein is implicit in its primary sequence, but to predict that conformationis no easy task. Now, George D. Rose and his colleague, Rajgopal Srinivasan, (Johns Hopkins University, Baltimore, MD, USA) have developed a remarkably successful algorithm for predictingthe folding pattem of monomeric,soluble globular proteins [Srinivasan, R. and Rose, G.D. (1995) Proteht Struct. Funct. Genet. 22, 81-99]. The program, dubbed LINUS (for Local Independently Nucleated Units of Structure), in honor of the late Linus Pauling, requires several days of calculationson a UnixrM-basedworkstation to predict the structure of a protein of 100 residues. The results on test proteins are comparable in quality to a low-resolution determination of structure by X-ray crystallography, which would typically require several months to do. LINUS proceeds repeatedly through the polypeptidechain from the N- to the C terminus, generating random conformations by perturbing the bond angles in groups of three adjacent residues at a time. Each new conformation is compared with the previous one, and accepted or
rejected on the basis of a highly simplified energy function, which includes hard-sphererepulsion(the 'bump check'), hydrogenbonding and the tendency for hydrophobic side chains to be buried inside the molecule. Conformations of greater than minimum energy are sometimes accepted, using a Monte Carlo procedure, in order to bounce the structure out of local energy minima. The structures of the amino acid side chains are simplified; for example, phenylalanine,tryptophan and tyrosine are all approximated by the same side chain consisting of just two pseudo-atoms. At first, the interaction interval, or distance over which residues can 'feel' each other, is limited to six residues. After 5000 cycles through the sequence with an interaction interval of six, the conformations generated are classified as helix, sheet, turn or loop. Any chain segment that assumes a single structure at least 70% of the time is frozen in that configuration, after which the interaction interval is increased to 12 and the chain-perturbation process is repeated. Any chain segment that adopts a given conformation in 70% of the trials at a given interactionintervalis frozen
disease characterized by a rash and, in more severe forms, it may also involve nail dystrophy and inflammatory arthritis. Associated psychological problems can have a very adverse effect on patients' quality of life. Despite the great efforts that have been made to understand the nature of this disease, it is surprising that we still know so little. There are no good animal models, and drug development has largely been a 'hit-or-miss' affair. The most promising recent advance has been the introduction of vitamin D analogues, particularly calcipotriol. Mike Cork, Franco di Giovine and Gordon Duff (Dermatology and Molecular Medicine Sections of the Department of Medicine and Pharmacology, University of Sheffield, UK), have been studying the molecular basis of psoriasis in the hope that this will be the best way to discover an effective treatment. At the recent annual meeting of the British Association of Dermatologists*, Cork described their discovery of a functional
with psoriasis. Earlier, the group had found an association between a polymorphism in the IL-1 receptor antagonist gene (IL-1RA) and psoriasis and turned their attention to another polymorphism in exon 5 of the IL-1 [3gene. They have screened a normal population of 198 subjects using PCR and restriction enzyme analysis and found that the frequency of the rare allele is0.17. They have also studied the polymorphism through three generations of a family and found that it follows normal Mendelian segregation. The rare allele of this polymorphism was associated with high production of IL-1[3 protein. They have now investigated a group of 180 patients with psoriasis attending a local out-patient clinic and found a higher frequency of the rarer allele of 0.30, with carriage increased from 0.33 to *Annual meeting of the British Association of Dermatologists, Glasgow, UK, 4--8 July 1995.
in place.After each set of 5000 trials, the interaction interval is increased by six, until it encompasses the entire protein. The entire process is called 'folding by hierarchic condensation'. Implicit in the procedure are assumptions that highly stable interactionsbetween nearby residues are more important than long-range interaction, that the precise structure of side chains is not essential to the overall folding pattern, and that the native conformations are robust and overdetermined, rather than, as others have surmised, precarionsly poised. Rose and Srinivasan have not adapted their program to membrane proteins; there would be few known structures with which to check the results. Nor are they soliciting protein sequences to test. They are refining the program, hoping to make it run faster and on less-powerfulcomputers, so others will be able to use it to esthnate folding patterns for the thousands of protein sequences now pouring into databases, thereby providing clues about their function. Paul M. Rowe
individuals in the under-30-yearsold grgup had a higher frequencyof the rarer allele (0:34) compared with those in the over-40-years old group (0.27). This is the first report of a genetic association with psoriasis in which function has been demonstrated, and it reinforces the current hypothesis that IL-1 genes play a significant role in the pathogenesis of the disease. According to Cork, increased cytokine levels lead to more inflammation, which is the major characteristic of the condition. The new vitamin D analogues antagonize the actions of IL-I and it may be that these genes confer a susceptibility to developing psoriasis, and thus their characterization may help identify at-risk individuals..In Cork's opinion: 'understanding the genetic component of polymorphism will lead to the development of more specific therapies'. Let's hope he is right. David B. Jack m
©1995, Elsevier Science Ltd
257