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1 Computational Biology and Bioinformatics Program, and 2 Developmental Biology Program, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia3 Bioinformatics and Pattern Discovery Group, IBM T.J. Watson Research Center, Yorktown Heights, NY 10598, USA4 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA5 Schools of Biotechnology & Biomolecular Sciences, and Medical Sciences, and 6 St. Vincent’s Clinical School, University of New South Wales, NSW 2052, Australia
(RECEIVED November 9, 2004; FINAL REVISION December 21, 2004; ACCEPTED December 22, 2004)
EGF domains are extracellular protein modules cross-linked by three intradomain disulfides. Past studies suggest the existence of two types of EGF domain with three-disulfides, human EGF-like (hEGF) domains and complement C1r-like (cEGF) domains, but to date no functional information has been related to the two different types, and they are not differentiated in sequence or structure databases. We have developed new sequence patterns based on the different C-termini to search specifically for the two types of EGF domains in sequence databases. The exhibited sensitivity and specificity of the new pattern-based method represents a significant advancement over the currently available sequence detection techniques. We re-annotated EGF sequences in the latest release of Swiss-Prot looking for functional relationships that might correlate with EGF type. We show that important post-translational modifications of three-disulfide EGFs, including unusual forms of glycosylation and post-translational proteolytic processing, are dependent on EGF subtype. For example, EGF domains that are shed from the cell surface and mediate intercellular signaling are all hEGFs, as are all human EGF receptor family ligands. Additional experimental data suggest that functional specialization has accompanied subtype divergence. Based on our structural analysis of EGF domains with three-disulfide bonds and comparison to laminin and integrin-like EGF domains with an additional inter-domain disulfide, we propose that these hEGF and cEGF domains may have arisen from a four-disulfide ancestor by selective loss of different cysteine residues.
Keywords: EGF; bidirectional signaling; fucosylation; RIP; shedding; HER tyrosine receptor kinase ligand; hydroxylation
Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041207005.
Reprint requests to: Merridee A. Wouters, Victor Chang Cardiac Research Institute, 384 Victoria St., Darlinghurst 2010, Sydney, NSW, Australia; e-mail: m.wouters{at}victorchang.unsw.edu.au; fax: +61-2-9295-8501.
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