Solution structure and peptide binding of the SH3 domain from human Fyn

Morton, Craig J.; Pugh, D.J.R.; Brown, Emma Lj; Kahmann, Jan D.; Renzoni, Debora; Campbell, Iain D.

doi:10.1016/s0969-2126(96)00076-7

Cited by 102 publications

(115 citation statements)

References 45 publications

(75 reference statements)

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“…Both¯exible regions are involved in crystal contacts. For the n-Src loop, a high mobility has also been observed in solution studies of single SH3 domains of Fyn (Morton et al, 1996) and the human MIA protein (Stoll et al, 2003) and in crystallographic and solution studies of the SH2/SH3 tandem domain from Fyn kinase (Arold et al, 2001;Ulmer et al, 2002).…”

Section: Description Of Domainsmentioning

confidence: 82%

Domain identification by iterative analysis of error-scaled difference distance matrices

Schneider

2004

Acta Crystallogr D Biol Cryst

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Iterative interpretation of error‐scaled difference distance matrices is suggested as a means of dividing a protein into structural domains on the basis of conformational differences between different models. Two conformers of Src kinase {PDB codes http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1fmk [Xu et al. (1997). Nature (London), 385, 595–602] and http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2src [Xu et al. (1999). Mol. Cell, 3, 629–638]} in the inactive state with and without a substrate analogue bound are analysed in order to demonstrate the approach. SH3, SH2 and the N‐ and C‐terminal lobes of the kinase domain are detected as structural modules that move with respect to each other. Notably, a relative movement between the SH3 and SH2 domains is detected although both structures of Src kinase are in the `assembled' state. Detailed analysis shows that Arg318, a residue topologically located in the N‐terminal lobe of the kinase domain, structurally belongs to the C‐terminal lobe. The movement of this residue together with the C‐terminal lobe upon substrate binding leads to the loss of a salt bridge between Arg318 and Asp117, a residue in the SH3 domain, providing an explanation for the increased mobility of the SH3 domain.

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Section: Description Of Domainsmentioning

confidence: 82%

Domain identification by iterative analysis of error-scaled difference distance matrices

Schneider

2004

Acta Crystallogr D Biol Cryst

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“…As is the case for most SH3 domains, some highly disorder N-and C-terminal residues have not been modelled due to lack of electronic density. The SH3 domain of c-Yes shares the b-barrel fold described for other SH3 domains consisting of two orthogonal b-sheets containing five anti-parallel strands connected by a turn of 3 10 -helix and three loops: the RT loop that connects strands b1 and b2, the n-Src loop that connects strands b2 and b3 and the distal loop, which connects strands b3 and b4. As illustrated in Fig.…”

Section: Crystal Structure Of C-yes Sh3 Domainmentioning

confidence: 98%

“…However, although several structures of the SH3 domains from the Src family both unliganded and complexed with ligands are currently available [4][5][6][7][8][9][10][11], no structural information has been reported for the SH3 domain of c-Yes. We present here the first high-resolution structure of the unliganded c-Yes SH3 domain obtained by X-ray crystallography.…”

Section: Introductionmentioning

confidence: 99%

Crystallographic structure of the SH3 domain of the human c‐Yes tyrosine kinase: Loop flexibility and amyloid aggregation

et al. 2007

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SH3 domains from the Src family of tyrosine kinases represent an interesting example of the delicate balance between promiscuity and specificity characteristic of proline-rich ligand recognition by SH3 domains. The development of inhibitors of therapeutic potential requires a good understanding of the molecular determinants of binding affinity and specificity and relies on the availability of high quality structural information. Here, we present the first high-resolution crystal structure of the SH3 domain of the c-Yes oncogen. Comparison with other SH3 domains from the Src family revealed significant deviations in the loop regions. In particular, the n-Src loop, highly flexible and partially disordered, is stabilized in an unusual conformation by the establishment of several intramolecular hydrogen bonds. Additionally, we present here the first report of amyloid aggregation by an SH3 domain from the Src family.

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“…The overall three dimensional structure of the SH3 domain of various proteins is similar, although di erences in sequence among them exist Hiroaki et al, 1996;Morton et al, 1996;Musacchio et al, 1994;Sicheri et al, 1997;Wittekind et al, 1997;Xu et al, 1997;Yu et al, 1992Yu et al, , 1994. In general, the SH3 domain consists of ®ve antiparallel b strands (a to e) that pack to form two perpendicular b sheets.…”

Section: Transforming Potential Of Mutant Vav Sh3c Proteinsmentioning

confidence: 99%

Mutagenic analysis of Vav reveals that an intact SH3 domain is required for transformation

et al. 1998

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The vav proto-oncogene encodes a protein with multiple modulae domains that enable it to function as a mediator, linking tyrosine signaling to downstream events in hematopoietic cells. Circumstantial evidence suggests that protein-protein interactions exerted by two of these domains, the Src homology 2 (SH2) and the Src homology 3 (SH3), play an important role in the regulation of Vav activity. To study the relevance of the SH3 domain for the function of vav as a transforming gene, we have created several mutations in the SH3 domain located at its carboxy region. Substitution of the non-conserved aspartic acid 797 (to asparagine, D797N) retained the transforming potential of the vav oncogene, whereas substitutions of ®ve highly conserved amino-acids: alanine 789 (to asparagine, A789N), leucine 801 (to arginine, L801R), tryptophan 821 (to arginine, W821R), glycine 830 (to valine, G830V) and valine 837 (to glutamic acid, V837E) greatly reduced its transforming potential. The mutant proteins resemble Vav in many biochemical properties; however, while the transforming mutant protein (D797N) associates with several unidenti®ed proteins in a manner similar to that of Vav, the non-transforming mutant Vav proteins react very poorly with these proteins. Among the known Vav-interacting proteins, hnRNP-K associates with all mutant proteins except A789N and V837E whereas binding of Zyxin to any of the mutant proteins is not a ected. Taken together, our results clearly demonstrate that the SH3 domain has a positive e ect on vav activity and is needed for vav transformation. The vavSH3C associating protein(s) that are crucial for its activity as a transforming gene have probably not yet been identi®ed.

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Solution structure and peptide binding of the SH3 domain from human Fyn

Cited by 102 publications

References 45 publications

Domain identification by iterative analysis of error-scaled difference distance matrices

Domain identification by iterative analysis of error-scaled difference distance matrices

Crystallographic structure of the SH3 domain of the human c‐Yes tyrosine kinase: Loop flexibility and amyloid aggregation

Mutagenic analysis of Vav reveals that an intact SH3 domain is required for transformation

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