Group:MUZIC:ALP

Introduction

The ALP subfamily (α-Actinin-associated LIM domain Proteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in vertebrates. Protein members of this subfamily include: CLP36 (also known as PDLIM1 or hCLIM1 (in human)^[1] and Elfin (in mouse)^[2]), Mystique (aka PDLIM2 or SLIM)^[3][4], ALP (aka PDLIM3)^[5] and RIL (aka PDLIM4).

On the basis of structural similarities, the ALP subfamily are related to the Enigma subfamily, possessing PDZ and LIM domains, as well as internal motifs viz ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the Enigma subfamily as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.

hCLIM1/CLP36 (C-terminal LIM Protein 36 kDa)^[6] and RIL (Reversion-Induced LIM)^[7] were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart ^[5] which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL ^[8]. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.

Sequence annotation

Domain map in the first isoforms of human ALP subfamily members: ALP [1] Mystique [2] RIL [3] hCLIM1[4]

ALP (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal

muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [5]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2.

Mystique, identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid^[9]. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[6].

RIL protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[7].

hCLIM1 also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [8].

Structures

Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity ^[10]. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.

• (2pkt) [9]

• (3pdv)[10]

• (1x64)[11]

• (1v51)[12]

• (2v1w)[13]

Function and Interactions

All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner has recently been identified; the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) peptide^[10]. An elegant summary of other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M et al (2010) ^[8] and te Velthius A.J. et al (2007) ^[11].

Pathology

Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily^[11], ^[8]. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the bird flu virus.

References

1. ↑ Kotaka M, Ngai SM, Garcia-Barcelo M, Tsui SK, Fung KP, Lee CY, Waye MM. Characterization of the human 36-kDa carboxyl terminal LIM domain protein (hCLIM1). J Cell Biochem. 1999 Feb 1;72(2):279-85. PMID:10022510
2. ↑ Kotaka M, Lau YM, Cheung KK, Lee SM, Li HY, Chan WY, Fung KP, Lee CY, Waye MM, Tsui SK. Elfin is expressed during early heart development. J Cell Biochem. 2001 Aug 21-Sep 5;83(3):463-72. PMID:11596114
3. ↑ Torrado M, Senatorov VV, Trivedi R, Fariss RN, Tomarev SI. Pdlim2, a novel PDZ-LIM domain protein, interacts with alpha-actinins and filamin A. Invest Ophthalmol Vis Sci. 2004 Nov;45(11):3955-63. PMID:15505042 doi:10.1167/iovs.04-0721
4. ↑ Loughran G, Healy NC, Kiely PA, Huigsloot M, Kedersha NL, O'Connor R. Mystique is a new insulin-like growth factor-I-regulated PDZ-LIM domain protein that promotes cell attachment and migration and suppresses Anchorage-independent growth. Mol Biol Cell. 2005 Apr;16(4):1811-22. Epub 2005 Jan 19. PMID:15659642 doi:10.1091/mbc.E04-12-1052
5. ↑ ^{5.0 5.1} Xia H, Winokur ST, Kuo WL, Altherr MR, Bredt DS. Actinin-associated LIM protein: identification of a domain interaction between PDZ and spectrin-like repeat motifs. J Cell Biol. 1997 Oct 20;139(2):507-15. PMID:9334352
6. ↑ Wang H, Harrison-Shostak DC, Lemasters JJ, Herman B. Cloning of a rat cDNA encoding a novel LIM domain protein with high homology to rat RIL. Gene. 1995 Nov 20;165(2):267-71. PMID:8522188
7. ↑ Kiess M, Scharm B, Aguzzi A, Hajnal A, Klemenz R, Schwarte-Waldhoff I, Schafer R. Expression of ril, a novel LIM domain gene, is down-regulated in Hras-transformed cells and restored in phenotypic revertants. Oncogene. 1995 Jan 5;10(1):61-8. PMID:7824279
8. ↑ ^{8.0 8.1 8.2} 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
9. ↑ 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
10. ↑ ^{10.0 10.1} Yu J, Li X, Wang Y, Li B, Li H, Li Y, Zhou W, Zhang C, Wang Y, Rao Z, Bartlam M, Cao Y. PDlim2 selectively interacts with the PDZ binding motif of highly pathogenic avian H5N1 influenza A virus NS1. PLoS One. 2011;6(5):e19511. Epub 2011 May 23. PMID:21625420 doi:10.1371/journal.pone.0019511
11. ↑ ^{11.0 11.1} 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