Group:MUZIC:ZASP

From Proteopedia

Jump to: navigation, search

Contents

LIM domain-binding protein 3 (ZASP)

Introduction

The LIM domain-binding protein 3 (LDB-3) or Z-disc Alternatively Spliced PDZ-domain containing (ZASP) protein is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells[1], as well as integrin adhesion sites in insect tissues[2]. ZASP is a major component protein of the striated muscle Z-disc and a member of the enigma family of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has been recently reported to interact with the PDZ-binding motifs in α-actinin-2, myotilin and myozenin[3]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities[4]. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites [2].

Sequence annotation

Six alternatively spliced isoforms have been identified in human (UniProt:O75112).

Domain organization in the first, canonical isoform of human ZASP
Domain organization in the first, canonical isoform of human ZASP

Structure

The solution structure of ZASP PDZ domain revealed a canonical PDZ domain fold containing six β-strands and two α-helices in a circular permutation mode common to PDZ domains[5]. The structure of ZASP LIM domain(s) is presently unknown, neither is there an experimental structure for ZASP PDZ domain fused with one or two of its binding partners

NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1rgw) [1]

Drag the structure with the mouse to rotate
.

Function and Interactions

PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the oracle of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. A recent report on the interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs[3] from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 [4]. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction [6].

Pathology

Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies[7]. Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans[8]. The presence of multiple mutations in the ZASP gene in patients with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states[9]; this possibly presents ZASP as a prominent marker of cardiac dysfunction with diagnostic importance. Mutations in ZASP have recently been linked to a novel form of muscular dystrophy in humans[10]. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal, most likely due to functional failure in multiple striated muscle types that displayed disorganised and fragmented Z-lines in skeletal and cardiac muscle[11][12]. Similarly, dis-organisation of integrin-adhesion sites was observed in insect tissues lacking in ZASP[2].

References

  1. ↑ Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G. ZASP: a new Z-band alternatively spliced PDZ-motif protein. J Cell Biol. 1999 Jul 26;146(2):465-75. PMID:10427098
  2. ↑ 2.0 2.1 2.2 Jani K, Schock F. Zasp is required for the assembly of functional integrin adhesion sites. J Cell Biol. 2007 Dec 31;179(7):1583-97. doi: 10.1083/jcb.200707045. PMID:18166658 doi:10.1083/jcb.200707045
  3. ↑ 3.0 3.1 von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A, Valle G, Carpen O, Faulkner G. A class III PDZ binding motif in the myotilin and FATZ families binds enigma family proteins: a common link for Z-disc myopathies. Mol Cell Biol. 2009 Feb;29(3):822-34. Epub 2008 Dec 1. PMID:19047374 doi:10.1128/MCB.01454-08
  4. ↑ 4.0 4.1 Klaavuniemi T, Ylanne J. Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with alpha-actinin--analysis of patient mutations. Exp Cell Res. 2006 May 1;312(8):1299-311. Epub 2006 Feb 14. PMID:16476425 doi:10.1016/j.yexcr.2005.12.036
  5. ↑ Au Y, Atkinson RA, Guerrini R, Kelly G, Joseph C, Martin SR, Muskett FW, Pallavicini A, Faulkner G, Pastore A. Solution structure of ZASP PDZ domain; implications for sarcomere ultrastructure and enigma family redundancy. Structure. 2004 Apr;12(4):611-22. PMID:15062084 doi:10.1016/j.str.2004.02.019
  6. ↑ Zhou Q, Ruiz-Lozano P, Martone ME, Chen J. Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C. J Biol Chem. 1999 Jul 9;274(28):19807-13. PMID:10391924
  7. ↑ Griggs R, Vihola A, Hackman P, Talvinen K, Haravuori H, Faulkner G, Eymard B, Richard I, Selcen D, Engel A, Carpen O, Udd B. Zaspopathy in a large classic late-onset distal myopathy family. Brain. 2007 Jun;130(Pt 6):1477-84. Epub 2007 Mar 2. PMID:17337483 doi:10.1093/brain/awm006
  8. ↑ Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G, Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. PMID:14662268
  9. ↑ Leung MC, Hitchen PG, Ward DG, Messer AE, Marston SB. Z-band alternatively spliced PDZ-motif protein (ZASP) is the major O-linked-beta-N-acetylglucosamine-substituted protein in human heart myofibrils. J Biol Chem. 2012 Dec 27. PMID:23271734 doi:10.1074/jbc.M112.410316
  10. ↑ Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005 Feb;57(2):269-76. PMID:15668942 doi:10.1002/ana.20376
  11. ↑ Zhou Q, Chu PH, Huang C, Cheng CF, Martone ME, Knoll G, Shelton GD, Evans S, Chen J. Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. J Cell Biol. 2001 Nov 12;155(4):605-12. Epub 2001 Nov 5. PMID:11696561 doi:10.1083/jcb.200107092
  12. ↑ te Velthuis AJ, Bagowski CP. PDZ and LIM domain-encoding genes: molecular interactions and their role in development. ScientificWorldJournal. 2007 Sep 1;7:1470-92. PMID:17767364 doi:10.1100/tsw.2007.232

Proteopedia Page Contributors and Editors (what is this?)

Adekunle Onipe, Nikos Pinotsis, Michal Harel, Jaime Prilusky

Retrieved from "http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP"
Personal tools