SH3 domain ligand binding: What's the consensus and where's the specificity?

Saksela, Kalle; Permi, Perttu

doi:10.1016/j.febslet.2012.04.042

Cited by 220 publications

(235 citation statements)

References 28 publications

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“…The Dynamin PRD Utilizes Both Short and Long Range Sequence Elements to Recognize Syndapin-The molecular basis for recognition of PXXP motifs by SH3 domains is well known (31)(32)(33), but our study extends this understanding in the case of the interaction between dynamin and syndapin, two proteins that are essential for normal synaptic vesicle endocytosis in mammals.…”

Section: Discussionmentioning

confidence: 73%

The Binding of Syndapin SH3 Domain to Dynamin Proline-rich Domain Involves Short and Long Distance Elements

Luo

Xue

Kwan

et al. 2016

Journal of Biological Chemistry

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Dynamin is a GTPase that mediates vesicle fission during synaptic vesicle endocytosis. Its long C-terminal proline-rich domain contains 13 PXXP motifs, which orchestrate its interactions with multiple proteins. The SH3 domains of syndapin and endophilin bind the PXXP motifs called Site 2 and 3 (Pro-786 -Pro-793) at the N-terminal end of the proline-rich domain, whereas the amphiphysin SH3 binds Site 9 (Pro-833-Pro-836) toward the C-terminal end. In some proteins, SH3/peptide interactions also involve short distance elements, which are 5-15 amino acid extensions flanking the central PXXP motif for high affinity binding. Here we found two previously unrecognized elements in the central and the C-terminal end of the dynamin proline-rich domain that account for a significant increase in syndapin binding affinity compared with a previously reported Site 2 and Site 3 PXXP peptide alone. The first new element (Gly-807-Gly-811) is short distance element on the C-terminal side of Site 2 PXXP, which might contact a groove identified under the RT loop of the SH3 domain. The second element (Arg-838 -Pro-844) is located about 50 amino acids downstream of Site 2. These two elements provide additional specificity to the syndapin SH3 domain outside of the well described polyproline-binding groove. Thus, the dynamin/syndapin interaction is mediated via a network of multiple contacts outside the core PXXP motif over a previously unrecognized extended region of the proline-rich domain. To our knowledge this is the first example among known SH3 interactions to involve spatially separated and extended long-range elements that combine to provide a higher affinity interaction. Dynamin is a large GTPase that is a central component of a variety of endocytic processes, including synaptic vesicle endocytosis and activity-dependent bulk endocytosis pathways in nerve terminals (1, 2). It is thought to be recruited to sites of endocytosis through interactions between its C-terminal proline-rich domain (PRD)5 and the SH3 domains of a variety of proteins (3). This set of partner proteins includes several well known endocytic proteins as well as proteins that provide connections between dynamin and the actin cytoskeleton (4).SH3 domains are small protein-protein interaction units consisting of a ␤-sandwich with five strands; the strands are connected by three loops and a 3 10 helix (5, 6). SH3 domains predominantly bind proline-rich sequences containing a short and conserved PXXP motif (where X represents any amino acid), as well as a flanking basic residue(s) such as arginine or lysine within 2-4 amino acids on either side of the PXXP motif. We term this 6 -8-residue sequence the core PXXP motif. PXXP motifs most often adopt a left-handed type II polyproline (PPII) helix conformation and bind to a canonical hydrophobic pocket located between two short loops of the target SH3 domain, the so-called RT and the n-Src loops (5, 6). The partner can interact with the SH3 protein in either of the two opposite orientations, depending on the location of...

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Section: Discussionmentioning

confidence: 73%

The Binding of Syndapin SH3 Domain to Dynamin Proline-rich Domain Involves Short and Long Distance Elements

Luo

Xue

Kwan

et al. 2016

Journal of Biological Chemistry

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“…1B). Poly-Pro stretches and hydrophobic surface areas are typically protein binding sites (31,32), identifying this region as a potential interaction area for proteins or other sAC domains. In fact, in the crystal, part of this hydrophobic patch interacts with the extended N-terminal tail of a symmetry-related monomer (Fig.…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

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

123

215

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cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3−); it thereby serves as a cellular sensor for HCO3−, carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3− binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3− activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3− sensing and a basis for targeting this system with drugs.

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“…The cytoplasmic C-terminal domain of the human receptor contains a proline (P) and arginine (R)-rich region, including three PRR repeats, that may be organized spatially in overlapping segments and constitute a binding domain for Src homology 3 (SH3) proteins (Saksela & Permi 2012). SH3 domains, which are directly involved in protein-protein associations, are found, for example, within proteins implicated in signal transduction, such as tyrosine kinases.…”

Section: Structure-activity Relationships and Evolution Of Kissrsmentioning

confidence: 99%

MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

Pasquier¹,

Kamech²,

Lafont³

et al. 2014

Journal of Molecular Endocrinology

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Following the discovery of kisspeptin (Kiss) and its receptor (GPR54 or KissR) in mammals, phylogenetic studies revealed up to three Kiss and four KissR paralogous genes in other vertebrates. The multiplicity of Kiss and KissR types in vertebrates probably originated from the two rounds of whole-genome duplication (1R and 2R) that occurred in early vertebrates. This review examines compelling recent advances on molecular diversity and phylogenetic evolution of vertebrate Kiss and KissR. It also addresses, from an evolutionary point of view, the issues of the structure-activity relationships and interaction of Kiss with KissR and of their signaling pathways. Independent gene losses, during vertebrate evolution, have shaped the repertoire of Kiss and KissR in the extant vertebrate species. In particular, there is no conserved combination of a given Kiss type with a KissR type, across vertebrate evolution. The striking conservation of the biologically active ten-amino-acid C-terminal sequence of all vertebrate kisspeptins, probably allowed this evolutionary flexibility of Kiss/KissR pairs. KissR mutations, responsible for hypogonadotropic hypogonadism in humans, mostly occurred at highly conserved amino acid positions among vertebrate KissR. This further highlights the key role of these amino acids in KissR function. In contrast, less conserved KissR regions, notably in the intracellular C-terminal domain, may account for differential intracellular signaling pathways between vertebrate KissR. Cross talk between evolutionary and biomedical studies should contribute to further understanding of the Kiss/KissR structure-activity relationships and biological functions.

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SH3 domain ligand binding: What's the consensus and where's the specificity?

Cited by 220 publications

References 28 publications

The Binding of Syndapin SH3 Domain to Dynamin Proline-rich Domain Involves Short and Long Distance Elements

The Binding of Syndapin SH3 Domain to Dynamin Proline-rich Domain Involves Short and Long Distance Elements

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

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