| Structural highlights
Function
[DLG1_HUMAN] Essential multidomain scaffolding protein required for normal development (By similarity). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.
Tolerance of protein folding to a circular permutation in a PDZ domain.,Hultqvist G, Punekar AS, Morrone A, Chi CN, Engstrom A, Selmer M, Gianni S, Jemth P PLoS One. 2012;7(11):e50055. doi: 10.1371/journal.pone.0050055. Epub 2012 Nov 21. PMID:23185531[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ishidate T, Matsumine A, Toyoshima K, Akiyama T. The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene. 2000 Jan 20;19(3):365-72. PMID:10656683 doi:10.1038/sj.onc.1203309
- ↑ Godreau D, Vranckx R, Maguy A, Rucker-Martin C, Goyenvalle C, Abdelshafy S, Tessier S, Couetil JP, Hatem SN. Expression, regulation and role of the MAGUK protein SAP-97 in human atrial myocardium. Cardiovasc Res. 2002 Dec;56(3):433-42. PMID:12445884
- ↑ Laprise P, Viel A, Rivard N. Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. J Biol Chem. 2004 Mar 12;279(11):10157-66. Epub 2003 Dec 29. PMID:14699157 doi:10.1074/jbc.M309843200
- ↑ Xavier R, Rabizadeh S, Ishiguro K, Andre N, Ortiz JB, Wachtel H, Morris DG, Lopez-Ilasaca M, Shaw AC, Swat W, Seed B. Discs large (Dlg1) complexes in lymphocyte activation. J Cell Biol. 2004 Jul 19;166(2):173-8. PMID:15263016 doi:10.1083/jcb.200309044
- ↑ El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, Coulombe A, Jeromin A, Hatem SN. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009 Mar 27;104(6):758-69. doi: 10.1161/CIRCRESAHA.108.191007. Epub, 2009 Feb 12. PMID:19213956 doi:10.1161/CIRCRESAHA.108.191007
- ↑ Sabio G, Cerezo-Guisado MI, Del Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JS, Campbell DG, Centeno F, Cuenda A. p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010 Aug 1;123(Pt 15):2596-604. doi: 10.1242/jcs.066514. Epub 2010, Jul 6. PMID:20605917 doi:10.1242/jcs.066514
- ↑ Hultqvist G, Punekar AS, Morrone A, Chi CN, Engstrom A, Selmer M, Gianni S, Jemth P. Tolerance of protein folding to a circular permutation in a PDZ domain. PLoS One. 2012;7(11):e50055. doi: 10.1371/journal.pone.0050055. Epub 2012 Nov 21. PMID:23185531 doi:http://dx.doi.org/10.1371/journal.pone.0050055
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