Generation of ligand-receptor alliances by "SEA" module-mediated cleavage of membrane-associated mucin proteins - PubMed (original) (raw)

. 2002 Mar;11(3):698-706.

doi: 10.1110/ps.16502.

Michael A McGuckin, Stefanie J Williams, Amos Baruch, Merav Yoeli, Ravit Ziv, Liron Okun, Joseph Zaretsky, Nechama Smorodinsky, Iafa Keydar, Pavlos Neophytou, Martin Stacey, His-Hsien Lin, Siamon Gordon

Affiliations

Generation of ligand-receptor alliances by "SEA" module-mediated cleavage of membrane-associated mucin proteins

Daniel H Wreschner et al. Protein Sci. 2002 Mar.

Abstract

A mechanism is described whereby one and the same gene can encode both a receptor protein as well as its specific ligand. Generation of this receptor-ligand partnership is effected by proteolytic cleavage within a specific module located in a membrane resident protein. It is postulated here that the "SEA" module, found in a number of heavily O-linked glycosylated membrane-associated proteins, serves as a site for proteolytic cleavage. The subunits generated by proteolytic cleavage of the SEA module reassociate, and can subsequently elicit a signaling cascade. We hypothesize that all membrane resident proteins containing such a "SEA" module will undergo cleavage, thereby generating a receptor-ligand alliance. This requires that the protein subunits resulting from the proteolytic cleavage reassociate with each other in a highly specific fashion. The same SEA module that serves as the site for proteolytic cleavage, probably also contains the binding sites for reassociation of the resultant two subunits. More than one type of module can function as a site for proteolytic cleavage; this can occur not only in one-pass membrane proteins but also in 7-transmembrane proteins and other membrane-associated proteins. The proposal presented here is likely to have significant practical consequences. It could well lead to the rational design and identification of molecules that, by binding to one of the cleaved partners, will act either as agonists or antagonists, alter signal transduction and, hence, cellular behavior.

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Figures

Fig. 1.

Fig. 1.

MUC1 isoforms and their interactions. (A) MUC1 isoforms. N and C refer to the amino and carboxyl termini of the proteins. Regions common to the various MUC1 isoforms have the same colours and shadings. SP and VNTR refer to the signal peptide and variable number of tandem repeats, respectively. The splice donor and acceptor sites used to generate the MUC1/Y isoform are indicated by S.D. and S.A., respectively. The membrane proximal binding site is indicated by "MEM. Site," whereas the binding site of the large extracellular domain is designated "EX site." Both are contained within the SEA module. (B) Signaling initiated by the release and reassociation of the large extracellular domain.

Fig. 2.

Fig. 2.

Across species comparison of the MUC1/TM protein. The sequences were taken from Spicer et al. (1995). The conserved YQEL and GSVVV sites, also noted and discussed in Spicer et al. (1995), are highlighted and the site of cleavage is indicated.

Fig. 3.

Fig. 3.

Conserved SEA module sequences in other proteins upstream of the GSVVV site. The MUC1 (P15941, accession numbers in brackets), MUC3 (AF143373), MUC12 (AF147790), Interphotoreceptor proteoglycan 200 (AF173155), C. elegans MUC (CAB03861) are aligned for maximal homology. The conserved LED, YQEL, and GSVVV sites are highlighted and the interdigitating hydrophilic (yellow on red background) and hydrophobic (yellow on blue background) amino acids just upstream of the cleavage site (vertical downward facing arrow) are also indicated. The small print (green) amino acids in the MUC1, MUC3, and perlecan sequences indicate the splice sites. These are also shown by the red stars. Numbers next to the stars indicate the intron phase.

Fig. 4.

Fig. 4.

C. elegans SEA module-containing transmembrane protein. (A) Sequence of C. elegans SEA module-containing transmembrane protein. Yellow letters on a blue background indicate the leader signal peptide and transmembrane domains. The transfer stop signal immediately downstream to the transmembrane domain is written in bold, italic, underlined letters, and the cytoplasmic tyrosine residues are highlighted in red. White letters on a gray background indicate the SEA module juxtaposed upstream of the transmembrane. The conserved motifs within the SEA module are indicated by red letters on a yellow background. Yellow letters on a green background show the strings of threonine and serine residues, and the potential N-glycosylation sites are highlighted yellow on a red background. (B) Comparison of C. elegans SEA module-containing transmembrane protein with human MUC1. The two sequences are aligned for maximum similarity. Conservatively substituted amino acids are indicated by a plus sign. Note that all hydrophilic amino acids (K, R, D, and E) are considered conservative substitutions for each other.

Fig. 4.

Fig. 4.

C. elegans SEA module-containing transmembrane protein. (A) Sequence of C. elegans SEA module-containing transmembrane protein. Yellow letters on a blue background indicate the leader signal peptide and transmembrane domains. The transfer stop signal immediately downstream to the transmembrane domain is written in bold, italic, underlined letters, and the cytoplasmic tyrosine residues are highlighted in red. White letters on a gray background indicate the SEA module juxtaposed upstream of the transmembrane. The conserved motifs within the SEA module are indicated by red letters on a yellow background. Yellow letters on a green background show the strings of threonine and serine residues, and the potential N-glycosylation sites are highlighted yellow on a red background. (B) Comparison of C. elegans SEA module-containing transmembrane protein with human MUC1. The two sequences are aligned for maximum similarity. Conservatively substituted amino acids are indicated by a plus sign. Note that all hydrophilic amino acids (K, R, D, and E) are considered conservative substitutions for each other.

Fig. 5.

Fig. 5.

Proposed cleavage in the MUC12, MUC3, and MUC13 SEA modules. The various proteins are shown schematically. The amino-terminal barred region indicates the tandem repeat mucin domains of these proteins. TM and CYT designate the transmembrane and cytoplasmic domains. The MUC12, MUC3, and MUC13 all have EGF-like domains that bracket the SEA module.

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