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Title
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A duplicated motif controls assembly of zona pellucida domain proteins.
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Authors
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L.Jovine,
H.Qi,
Z.Williams,
E.S.Litscher,
P.M.Wassarman.
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Ref.
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Proc Natl Acad Sci U S A, 2004,
101,
5922-5927.
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PubMed id
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Abstract
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Many secreted eukaryotic glycoproteins that play fundamental roles in
development, hearing, immunity, and cancer polymerize into filaments and
extracellular matrices through zona pellucida (ZP) domains. ZP domain proteins
are synthesized as precursors containing C-terminal propeptides that are cleaved
at conserved sites. However, the consequences of this processing and the
mechanism by which nascent proteins assemble are unclear. By microinjection of
mutated DNA constructs into growing oocytes and mammalian cell transfection, we
have identified a conserved duplicated motif [EHP (external hydrophobic
patch)/IHP (internal hydrophobic patch)] regulating the assembly of mouse ZP
proteins. Whereas the transmembrane domain (TMD) of ZP3 can be functionally
replaced by an unrelated TMD, mutations in either EHP or IHP do not hinder
secretion of full-length ZP3 but completely abolish its assembly. Because
mutants truncated before the TMD are not processed, we conclude that the
conserved TMD of mammalian ZP proteins does not engage them in specific
interactions but is essential for C-terminal processing. Cleavage of ZP
precursors results in loss of the EHP, thereby activating secreted polypeptides
to assemble by using the IHP within the ZP domain. Taken together, these
findings suggest a general mechanism for assembly of ZP domain proteins.
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