Ubiquitin Binds to and Regulates a Subset of SH3 Domains

Stamenova, Svetoslava D.; French, Morris L. V.; He, Yuan; Francis, Smitha A.; Kramer, Zachary; Hicke, Linda A

doi:10.1016/j.molcel.2006.12.016

Cited by 72 publications

(108 citation statements)

References 51 publications

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“…Epsin favors binding to K63-polyubiquitin, which correlates well with the requirement of multiple Ubs as an internalization signal (Hawryluk et al 2006;Sato et al 2009). Other UBDs are present at sites of CME including ones in CIN85 and Hrs, and others are likely to be uncovered (Soubeyran et al 2002;Stamenova et al 2007;Mayers et al 2013). Because relatively few proteins have been assessed for Ub-dependent internalization, it is possible that these additional UBD-containing proteins operate as adaptors for different subsets of ubiquitinated proteins.…”

Section: How Ubiquitin Mediates Internalization From the Plasma Membranementioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

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Section: How Ubiquitin Mediates Internalization From the Plasma Membranementioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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“…S2). The ubiquitin SH3 binding site has little in common with conventional SH3 binding sites; it forms a structured β-sheet and does not carry a PXXP motif, yet it binds to the same hydrophobic groove on SH3 domains as PXXP binding peptides (25).…”

Section: Predicted Sh3 Binding Sites Have Distinct Structural and Evomentioning

confidence: 99%

“…SH3 domains fall generally into two classes recognizing peptides with fixed residues proline (P), lysine (K), and arginine (R), conforming, respectively, to [RK]XXPXXP and PXXPX[RK] (13). A number of alternative peptides have, however, been identified (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), such as the noncanonical peptides that bind to the Fus1 SH3 domain (15), and the structured β-sheet ubiquitin-like domain of Ubi4 that binds to the Sla1-3 SH3 domain (25). A number of in vitro methods have been applied to study preferences of SH3 domains for specific sequence patterns, i.e., motifs.…”

mentioning

confidence: 99%

Evolution of domain–peptide interactions to coadapt specificity and affinity to functional diversity

Kelil

Levy

Michnick

2016

Proc. Natl. Acad. Sci. U.S.A.

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Evolution of complexity in eukaryotic proteomes has arisen, in part, through emergence of modular independently folded domains mediating protein interactions via binding to short linear peptides in proteins. Over 30 years, structural properties and sequence preferences of these peptides have been extensively characterized. Less successful, however, were efforts to establish relationships between physicochemical properties and functions of domainpeptide interactions. To our knowledge, we have devised the first strategy to exhaustively explore the binding specificity of protein domain-peptide interactions. We applied the strategy to SH3 domains to determine the properties of their binding peptides starting from various experimental data. The strategy identified the majority (∼70%) of experimentally determined SH3 binding sites. We discovered mutual relationships among binding specificity, binding affinity, and structural properties and evolution of linear peptides. Remarkably, we found that these properties are also related to functional diversity, defined by depth of proteins within hierarchies of gene ontologies. Our results revealed that linear peptides evolved to coadapt specificity and affinity to functional diversity of domain-peptide interactions. Thus, domain-peptide interactions follow human-constructed gene ontologies, which suggest that our understanding of biological process hierarchies reflect the way chemical and thermodynamic properties of linear peptides and their interaction networks, in general, have evolved.linear peptides | domain-peptide interactions | binding specificity | binding affinity | functional specificity M any proteins, particularly in eukaryotes, are composed of modular protein architectures consisting of multiple independently folding domains (1). Specific domains such as SH3 and PDZ domains were repeatedly used throughout evolution in increasingly complex organisms to mediate protein-protein interactions involved in signal transduction and protein targeting (2-5). These domains are associated with a number of human diseases and are targets of virus and other pathogen virulence proteins (6). Functions of these domains include binding to sequence-specific peptides both among themselves and on other proteins. Such interactions can create enormous plasticity in complex signaling and regulatory networks on immediate to evolutionary timescales (7), and are often used for regulating the activities of proteins and the spatiotemporal organization of protein interaction networks (8,9). However, at the cellular level, we still do not grasp why certain peptides in proteins bind to distinct domains with high specificity whereas others highly cross-react with a number of members of a family of domains, and also what is the relationship between specificity of binding and specificity of functions of domain-peptide interactions. Two extreme examples are peptides of the MAPKK protein Pbs2 (residues 92-106) (10) and the actin assembly protein Las17 (residues 306-336) (11), which both interact with ...

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“…13 The recognition sequence of the CD2AP SH3 domains is unusual in that each domain has an exact requirement for the sequence PXXXPR, with a preference for PXPXPR sequences, 14 where the final arginine is critical for binding. 10 The SH3 domains are necessary for CD2AP interactions with a number of signaling molecules, regulators of the cytoskeleton, and modulators of apoptosis, including CD2, 1,10 SETA binding protein 1, 15 the tyrosine kinase negative regulator c-Cbl, 10,[16][17][18] ubiquitin ligase Cbl-b, 19 ADP-ribosylation factor GTPase-activating protein ASAP1, 20 apoptosis-linked gene 2-interacting protein X/apoptosis-linked gene 2-interacting protein 1, 21,22 and ubiquitin, 23 each of which contains the target recognition sequence within their cystosolic domains. Simultaneous interactions with multiple CD2AP SH3 domains have been postulated as necessary for receptor clustering and subsequent internalization.…”

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confidence: 99%

Structure of the Kidney Slit Diaphragm Adapter Protein CD2-Associated Protein as Determined with Electron Microscopy

Adair

Altintas

Möller

et al. 2014

Journal of the American Society of Nephrology

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CD2-associated protein (CD2AP) is a multidomain scaffolding protein that has a critical role in renal function. CD2AP is expressed in glomerular podocytes at the slit diaphragm, a modified adherens junction that comprises the protein filtration barrier of the kidney, and interacts with a number of protein ligands involved in cytoskeletal remodeling, membrane trafficking, cell motility, and cell survival. The structure of CD2AP is unknown. We used electron microscopy and single particle image analysis to determine the threedimensional structure of recombinant full-length CD2AP and found that the protein is a tetramer in solution. Image reconstruction of negatively stained protein particles generated a structure at 21 Å resolution. The protein assumed a roughly spherical, very loosely packed structure. Analysis of the electron density map revealed that CD2AP consists of a central coiled-coil domain, which forms the tetramer interface, surrounded by four symmetry-related motifs, each containing three globular domains corresponding to the three SH3 domains. The spatial organization exposes the binding sites of all 12 SH3 domains in the tetramer, allowing simultaneous binding to multiple targets. Determination of the structure of CD2AP provides novel insights into the biology of this slit diaphragm protein and lays the groundwork for characterizing the interactions between key molecules of the slit diaphragm that control glomerular filtration.

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Ubiquitin Binds to and Regulates a Subset of SH3 Domains

Cited by 72 publications

References 51 publications

Ubiquitin-Dependent Sorting in Endocytosis

Ubiquitin-Dependent Sorting in Endocytosis

Evolution of domain–peptide interactions to coadapt specificity and affinity to functional diversity

Structure of the Kidney Slit Diaphragm Adapter Protein CD2-Associated Protein as Determined with Electron Microscopy

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