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Information in the signal peptide?
J. theor. Biol. (1982) 99,831-833
LETTERTO
Information
THE EDITOR
in the Signal Peptide?
A hydrophobic sequence of 15 to 30 amino acids, the signal peptide, has been found at the amino terminus of most secretory or membrane proteins. It has been postulated that the signal peptide is rapidly cleaved by a membrane-associated protease in viva after it has functioned to guide the nascent protein from the ribosome, through the membrane and into the lumen of the rough endoplasmic reticulum (Blobel, et al., 1979). Properties of a signal recognition protein have been described; this protein binds with high affinity to nascent polysomes containing endoplasmic reticulumtargeted signal sequences in their nascent chains (Walter, Ibrahimi & Blobel, 1981; Walter & Blobel, 1981a; Walter & Blobel 1981b). Although known signal peptides are of hydrophobic character, they generally have little amino acid sequence homology. For example, growth hormone and prolactin exhibit extensive homology within their main primary structure with 161 identical amino acids out of 191, and with the same pattern of internal repeating sequences. Yet the signals of these two proteins have little homology. An example is known, however, in which two proteins share identical signal sequences, hen conalbumin and hen transferrin (Thibodeau, Lee & Palmiter, 1978). Perhaps this is a hint that the signal peptide is more than just a string of any hydrophobic amino acids; perhaps there is “information” in the signal peptide. These two proteins also may have similar oligosaccharide moieties since on a weight basis they have similar amounts of neutral sugars and acetylhexosamines. Conalbumin lacks sialic acid, which is present in transferrin; it is generally believed that sialic acid is added to glycoproteins at a late stage rather than co-translationally. Another less striking example of apparent homology between signal peptides exists. The recently published sequence for the signal peptide of the alpha subunit of human choriogonadotropin (Birken et al., 1981) appears to be homologous with that of the vesicular stomatitis virus glycoprotein (Lingappa et al., 1978). These sequences are shown in Fig. 1. The viral protein signal could be imagined to be a more compact copy; yet, the hormone subunit and the viral protein share no known evolutionary history. The similarity between these signal sequences might well be a chance occurrence. However, a computer analysis of the sequences kindly 831
0022%5193/82/240831+03
$03.00
@ 1982AcademicPress
Inc. (London)
Ltd.
832
J.
A.
MAGNER
LETTER
TO
THE
833
EDITOR
performed in the laboratory of Dr Harry Saroff at the National Institutes of Health showed that the similarity of the sequences is 2.2 standard deviations beyond what might be expected on the basis of chance alone; it should be noted, though, that the limit of three standard deviations is usually applied for homology studies, and that analyses of short sequences may be misleading. Of interest is that both vesicular stomatitis virus glycoprotein and the alpha subunit of human choriogonadotropin require co-translational processing, with the eventual addition of two complex-type oligosaccharides to each protein (Mizuochi & Kobata, 1980; Tabas, Schlesinger & Kornfeld, 1978). One might postulate that the genetic information for co-translational processing is expressed as an ordered cluster of enzymes near certain ribosome binding sites. A particular signal conformation might serve to guide those nascent chains that require a particular type of co-translational processing into the proper cluster of enzymes. Alternatively, others have postulated that the tertiary structure of nascent glycoproteins determines the course of co-translational and post-translational oligosaccharide alterations. Clearly such alterations are not random, and the information required for proper biosynthesis must be available at the biosynthetic site or sites in some form. Clinical Endocrinology Branch, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases Bethesda, Maryland 20205, U.S.A. (Received 8 June 1981, and in final form 2 August
JAMES
A.
MAGNER
1982)
REFERENCES BIRKEN,S.,FETHERSTON,J.,CANFIELD,R.&BOIME,I.(~~S~).J. biol.Chem.256,1816. BLOBEL, G., WALTER,P.,CHANG,C., GOLDMAN,B.,ERICKSON, A. & LINGAPPA, V. (1979). Symp. Sot. exp. Biol. 33,9. LINGAPPA,V.,KATZ,F.,LODISH,H.& BLOBEL,G.(~~~~). J. biol. Chem.253,8667. MIZLIOCHI, T. & KOBATA, A. (1980). Biochem. biovhvs. Res. Commun. 97,772. TABAS,I.,SCHLESINGER,S.,& KORNFELD,~. (19%&J. biol. Chem.253,716. THIBODEAIJ,S.,LEE.D. & PALMITER,R. (1978).-l, biol. Chem.253.3771. WALTER,P.,.IBRAHIMI, I. & BLOBEL,~. (i98l):J. Cell Biol. 91,545. WALTER,P.& BLOBEL, G.(1981a).J. CellBiol. 91,551. WALTER,~. & BLOBEL, G. (1981b).J. CellBiol. 91,557.
LETTERTO
Information
THE EDITOR
in the Signal Peptide?
A hydrophobic sequence of 15 to 30 amino acids, the signal peptide, has been found at the amino terminus of most secretory or membrane proteins. It has been postulated that the signal peptide is rapidly cleaved by a membrane-associated protease in viva after it has functioned to guide the nascent protein from the ribosome, through the membrane and into the lumen of the rough endoplasmic reticulum (Blobel, et al., 1979). Properties of a signal recognition protein have been described; this protein binds with high affinity to nascent polysomes containing endoplasmic reticulumtargeted signal sequences in their nascent chains (Walter, Ibrahimi & Blobel, 1981; Walter & Blobel, 1981a; Walter & Blobel 1981b). Although known signal peptides are of hydrophobic character, they generally have little amino acid sequence homology. For example, growth hormone and prolactin exhibit extensive homology within their main primary structure with 161 identical amino acids out of 191, and with the same pattern of internal repeating sequences. Yet the signals of these two proteins have little homology. An example is known, however, in which two proteins share identical signal sequences, hen conalbumin and hen transferrin (Thibodeau, Lee & Palmiter, 1978). Perhaps this is a hint that the signal peptide is more than just a string of any hydrophobic amino acids; perhaps there is “information” in the signal peptide. These two proteins also may have similar oligosaccharide moieties since on a weight basis they have similar amounts of neutral sugars and acetylhexosamines. Conalbumin lacks sialic acid, which is present in transferrin; it is generally believed that sialic acid is added to glycoproteins at a late stage rather than co-translationally. Another less striking example of apparent homology between signal peptides exists. The recently published sequence for the signal peptide of the alpha subunit of human choriogonadotropin (Birken et al., 1981) appears to be homologous with that of the vesicular stomatitis virus glycoprotein (Lingappa et al., 1978). These sequences are shown in Fig. 1. The viral protein signal could be imagined to be a more compact copy; yet, the hormone subunit and the viral protein share no known evolutionary history. The similarity between these signal sequences might well be a chance occurrence. However, a computer analysis of the sequences kindly 831
0022%5193/82/240831+03
$03.00
@ 1982AcademicPress
Inc. (London)
Ltd.
832
J.
A.
MAGNER
LETTER
TO
THE
833
EDITOR
performed in the laboratory of Dr Harry Saroff at the National Institutes of Health showed that the similarity of the sequences is 2.2 standard deviations beyond what might be expected on the basis of chance alone; it should be noted, though, that the limit of three standard deviations is usually applied for homology studies, and that analyses of short sequences may be misleading. Of interest is that both vesicular stomatitis virus glycoprotein and the alpha subunit of human choriogonadotropin require co-translational processing, with the eventual addition of two complex-type oligosaccharides to each protein (Mizuochi & Kobata, 1980; Tabas, Schlesinger & Kornfeld, 1978). One might postulate that the genetic information for co-translational processing is expressed as an ordered cluster of enzymes near certain ribosome binding sites. A particular signal conformation might serve to guide those nascent chains that require a particular type of co-translational processing into the proper cluster of enzymes. Alternatively, others have postulated that the tertiary structure of nascent glycoproteins determines the course of co-translational and post-translational oligosaccharide alterations. Clearly such alterations are not random, and the information required for proper biosynthesis must be available at the biosynthetic site or sites in some form. Clinical Endocrinology Branch, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases Bethesda, Maryland 20205, U.S.A. (Received 8 June 1981, and in final form 2 August
JAMES
A.
MAGNER
1982)
REFERENCES BIRKEN,S.,FETHERSTON,J.,CANFIELD,R.&BOIME,I.(~~S~).J. biol.Chem.256,1816. BLOBEL, G., WALTER,P.,CHANG,C., GOLDMAN,B.,ERICKSON, A. & LINGAPPA, V. (1979). Symp. Sot. exp. Biol. 33,9. LINGAPPA,V.,KATZ,F.,LODISH,H.& BLOBEL,G.(~~~~). J. biol. Chem.253,8667. MIZLIOCHI, T. & KOBATA, A. (1980). Biochem. biovhvs. Res. Commun. 97,772. TABAS,I.,SCHLESINGER,S.,& KORNFELD,~. (19%&J. biol. Chem.253,716. THIBODEAIJ,S.,LEE.D. & PALMITER,R. (1978).-l, biol. Chem.253.3771. WALTER,P.,.IBRAHIMI, I. & BLOBEL,~. (i98l):J. Cell Biol. 91,545. WALTER,P.& BLOBEL, G.(1981a).J. CellBiol. 91,551. WALTER,~. & BLOBEL, G. (1981b).J. CellBiol. 91,557.