Group:MUZIC:Enigma Family

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Enigma family: PDZ- and 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] which is found in mouse and also identified by independent researchers who named it 'Oracle'^[3]).

Didactically, protein members of the enigma subfamily typically possess within their structure: (1) an N-terminal PDZ domain (a domain which is named after the 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 domain (a domain which is named after the first three proteins where it was characterized i.e. Lin-11, Isl1 and Mec-3)^[4].

The 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 motor 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 have been suggested to be important for targeting/sustaining interacting protein complexes within the sarcomere for a physiologically functional muscle.

Sequence Annotation

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 protein with an N-terminal PDZ domain and three C-terminal LIM domains ^[6], ^[7]. Five alternatively spliced isoforms are presently identified [1]

Assembly of the PDZ- and LIM-domains of the first Enigma isoform identified and characterized (457 amino acids) is as illustrated below [Q9NR12] [2] ^[8]:

Image:Enigma.png

Enigma Homologue (ENH) protein

ZASP/Cypher/Oracle

Structure

Shown to the right, the X-ray crystal structure of Enigma PDZ domain has recently been solved to 1.11Å. This revealed a canonical PDZ-domain fold containing six strands and 2 helices.

Function and Interactions

Enigma proteinExperimental 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 [[^[9]]]. It has also been implicated in bone formation and fracture repair^[10]. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains^[11]. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner^[12]. The LIM-3 domain binds endocytic codes of INSR.

Enigma Homologue (ENH) protein

ZASP/Cypher/Oracle

Pathology

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. ↑ 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
7. ↑ 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
8. ↑ 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
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. ↑ 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
11. ↑ 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
12. ↑ 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

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