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Title: Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution

Abstract

The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline-rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the Shank3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well-characterized protein-protein interaction domain within the context of multi-domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3more » domain or its vicinity in the different Shank isoforms. - Highlights: • The SH3 domain from Shank3 was studied at sub-atomic resolution. • The Shank family has lost the canonical peptide-binding site of the SH3 domain. • The Shank SH3 domain may have lost or altered canonical SH3 domain functions.« less

Authors:
;  [1];  [2];  [1];  [3]
  1. Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu (Finland)
  2. Institute of Anatomy and Cell Biology, University of Ulm (Germany)
  3. (Norway)
Publication Date:
OSTI Identifier:
22719049
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 490; Journal Issue: 3; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; DISEASES; EVOLUTION; LIGANDS; MUTATIONS; PEPTIDES; PROLINE

Citation Formats

Ponna, Srinivas Kumar, Myllykoski, Matti, Boeckers, Tobias M., Kursula, Petri, and Department of Biomedicine, University of Bergen. Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.06.121.
Ponna, Srinivas Kumar, Myllykoski, Matti, Boeckers, Tobias M., Kursula, Petri, & Department of Biomedicine, University of Bergen. Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution. United States. doi:10.1016/J.BBRC.2017.06.121.
Ponna, Srinivas Kumar, Myllykoski, Matti, Boeckers, Tobias M., Kursula, Petri, and Department of Biomedicine, University of Bergen. Sat . "Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution". United States. doi:10.1016/J.BBRC.2017.06.121.
@article{osti_22719049,
title = {Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution},
author = {Ponna, Srinivas Kumar and Myllykoski, Matti and Boeckers, Tobias M. and Kursula, Petri and Department of Biomedicine, University of Bergen},
abstractNote = {The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline-rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the Shank3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well-characterized protein-protein interaction domain within the context of multi-domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3 domain or its vicinity in the different Shank isoforms. - Highlights: • The SH3 domain from Shank3 was studied at sub-atomic resolution. • The Shank family has lost the canonical peptide-binding site of the SH3 domain. • The Shank SH3 domain may have lost or altered canonical SH3 domain functions.},
doi = {10.1016/J.BBRC.2017.06.121},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 490,
place = {United States},
year = {2017},
month = {8}
}