Group:MUZIC:Enigma Family

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Contents

Introduction

Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton. Three member proteins have extensively been described and characterized within this subfamily: Enigma protein, Enigma Homologue (ENH) protein and ZASP/Cypher/Oracle (ZASP[1] being the human orthologue of cypher[2] in mouse, also identified by independent researchers as oracle[3]). The family name - Enigma - possibly was inspired by the intricately complicated splice variants identified in the first member, a common feature in all member proteins, as well as their redundant, indinstinct functions in the cytoskeleton. Didactically, protein members of the enigma subfamily typically possess within their structure: (1) an N-terminal PDZ domain (domain named after first three proteins where it was initially characterized i.e. PSD 95, Disc large protein and Zonula Occludens 1), and (2) three C-terminal LIM domains (domain named after three proteins where it was first characterized Lin-11, Isl1 and Mec-3)[4]. The Enigma member proteins have all been located to the mammalian muscle cells, some specific to the heart and skeletal muscle Z-disk. They interact via their PDZ domains with protein components of the Z-disk and also recruit signalling molecules via their LIM domains or internal motifs, for example ZM motif (ZASP-like motif which is sandwiched between the PDZ- and LIM-domains in ZASP)[5]. These interactions via their PDZ- and LIM-domains suggest roles important for targeting/sustaining interacting protein complexes within the myofibrillar sarcomere for a physiologically functional muscle.

Sequence annotation

PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members: ZASP [1]ENH [2]Enigma [3]
PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members: ZASP [1]ENH [2]Enigma [3]

ZASP (Z-disk Alternatively Spliced PDZ domain protein), also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal muscle[6]. Five alternatively spliced isoforms of ZASP have been identified (UniProtKB: O75112)[4]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 [7].

Enigma Homologue (ENH) protein, also referred to as PDLIM5, is ~67 kDa, 596-amino-acid human ortholog of rat ENH protein [8] with four alternatively spliced isoforms (UniProtKB ID: Q96HC4)[5].

Enigma protein alternatively referred to as PDLIM7 (PDZ and LIM domain protein 7) is the first and representative member of the Enigma subfamily. Initially characterized in human as ~49.85 kDa, 457 amino-acid protein with an N-terminal PDZ domain and three C-terminal LIM domains [9] [10]. Five alternatively spliced isoforms are presently identified (UniProtKB ID: Q9NR12)[6].

Structure

NMR solution structure of LIM-1 domain of Enigma Homologue protein (PDB ID: 2dar) [1]

Drag the structure with the mouse to rotate

X-ray crystal structure of PDZ domain of Enigma protein at 1.11Å (PDB ID: 2q3g [1]

Drag the structure with the mouse to rotate

Molecular structures of PDZ domain(s) of the three member proteins have recently been solved. Likewise, the LIM-1 domain of Enigma Homologue protein has yielded its structure in atomic details. Structural model of all member proteins reveal canonical PDZ domain fold containing six β-strands (A-F) and 2 α-helices (A and B) [7]

Function and Interactions

In general, the PDZ domain(s) of Enigma subfamily have been structurally revealed as a classical class I PDZ domain - this is suggested by its interaction with the C-terminal region of α-actinin-2 [11]. Recently, it has been shown that the PDZ domains of Enigma subfamily proteins also interacts with Myotilin and Calsarcin/FATZ C-terminal motifs, which have the characteristics of class III PDZ-binding domain sequences [12]. Moreover, the LIM domain(s) of Enigma subfamily proteins interact with different domains in various proteins, particularly in signaling factors. This common structural feature supports the notion that Enigma proteins serve as adaptor proteins, where the PDZ domain tethers the protein to the cytoskeleton and the LIM domain or additional internal domains (ZM-motif), recruit signaling proteins to implement corresponding functions (see [13], and references therein). In addition, experimental evidences indicate Enigma protein may function as a scaffold on which the coordinated assembly of sarcomeric proteins can occur; largely owing to the interactions via its PDZ- and LIM domains with actin-associated proteins of cardiac and skeletal muscle, as well as non-muscle tissues [[[14]]]. It has also been implicated in bone formation and fracture repair[15]. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains[16]. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner[17]. Despite the co-localization of Enigma protein with proteins in the Z-line and I-band, a definite functional role in the sarcomere has not been shown yet[18]; which resounds the literal meaning of the word Enigma.

Pathology

Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans [19]. 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. Recently, mutations in ZASP have been linked to a novel form of muscular dystrophy in humans[20]. The expression studies of Maeno-Hikichi et al., who found the ENH protein expressed in various regions of the brain, suggest a possible role in brain development[21]. In accordance, ENH expression levels were found to be significantly increased in all brain regions of patients with bipolar disorder, schizophrenia, and major depression(see [22], and references therein).

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. ↑ 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
  3. ↑ Passier R, Richardson JA, Olson EN. Oracle, a novel PDZ-LIM domain protein expressed in heart and skeletal muscle. Mech Dev. 2000 Apr;92(2):277-84. PMID:10727866
  4. ↑ Zheng M, Cheng H, Banerjee I, Chen J. ALP/Enigma PDZ-LIM domain proteins in the heart. J Mol Cell Biol. 2010 Apr;2(2):96-102. Epub 2009 Dec 30. PMID:20042479 doi:10.1093/jmcb/mjp038
  5. ↑ Wang X, Su H. Unraveling enigma in the z-disks. Circ Res. 2010 Aug 6;107(3):321-3. PMID:20689070 doi:10.1161/CIRCRESAHA.110.225615
  6. ↑ 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
  7. ↑ 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
  8. ↑ Ueki N, Seki N, Yano K, Masuho Y, Saito T, Muramatsu M. Isolation, tissue expression, and chromosomal assignment of a human LIM protein gene, showing homology to rat enigma homologue (ENH). J Hum Genet. 1999;44(4):256-60. PMID:10429367 doi:10.1007/s100380050155
  9. ↑ Wu RY, Gill GN. LIM domain recognition of a tyrosine-containing tight turn. J Biol Chem. 1994 Oct 7;269(40):25085-90. PMID:7929196
  10. ↑ Guy PM, Kenny DA, Gill GN. The PDZ domain of the LIM protein enigma binds to beta-tropomyosin. Mol Biol Cell. 1999 Jun;10(6):1973-84. PMID:10359609
  11. ↑ 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
  12. ↑ 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
  13. ↑ Zheng M, Cheng H, Banerjee I, Chen J. ALP/Enigma PDZ-LIM domain proteins in the heart. J Mol Cell Biol. 2010 Apr;2(2):96-102. Epub 2009 Dec 30. PMID:20042479 doi:10.1093/jmcb/mjp038
  14. ↑ Wu RY, Gill GN. LIM domain recognition of a tyrosine-containing tight turn. J Biol Chem. 1994 Oct 7;269(40):25085-90. PMID:7929196
  15. ↑ Liu Y, Hair GA, Boden SD, Viggeswarapu M, Titus L. Overexpressed LIM mineralization proteins do not require LIM domains to induce bone. J Bone Miner Res. 2002 Mar;17(3):406-14. PMID:11874232
  16. ↑ Kuroda S, Tokunaga C, Kiyohara Y, Higuchi O, Konishi H, Mizuno K, Gill GN, Kikkawa U. Protein-protein interaction of zinc finger LIM domains with protein kinase C. J Biol Chem. 1996 Dec 6;271(49):31029-32. PMID:8940095
  17. ↑ Durick K, Gill GN, Taylor SS. Shc and Enigma are both required for mitogenic signaling by Ret/ptc2. Mol Cell Biol. 1998 Apr;18(4):2298-308. PMID:9528800
  18. ↑ Zheng M, Cheng H, Banerjee I, Chen J. ALP/Enigma PDZ-LIM domain proteins in the heart. J Mol Cell Biol. 2010 Apr;2(2):96-102. Epub 2009 Dec 30. PMID:20042479 doi:10.1093/jmcb/mjp038
  19. ↑ 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
  20. ↑ 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
  21. ↑ Maeno-Hikichi Y, Chang S, Matsumura K, Lai M, Lin H, Nakagawa N, Kuroda S, Zhang JF. A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels. Nat Neurosci. 2003 May;6(5):468-75. PMID:12665800 doi:10.1038/nn1041
  22. ↑ 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

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