Group:MUZIC:ALP

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ALP subfamily: PDZ/LIM domain proteins of the cytoskeleton

On the basis of structural similarities, the ALP (α-Actinin-associated LIM domain Proteins) subfamily are related to the Enigma subfamily [5], containing PDZ/LIM-domains [6][7]), 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 an N-terminal PDZ domain and only one C-terminal LIM domain. Four proteins: ALP (PDLIM3)[1], CLP36(hCLIM1(human)[2], Elfin (mouse)[3], PDLIM1), RIL(PDLIM4) and Mystique[4],[5] (SLIM, PDLIM2) have been classified into the ALP subfamily.

CLP36 (C-terminal LIM Protein 36 kDa)[6] and RIL (Reversion-Induced LIM)[7] protein were the first to be characterized. 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 [8], which shares a high degree of homology with previously characterized CLP36 and RIL proteins[9].

Sequence annotation and domain organization

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


Apart from the PDZ/LIM domains, all ALP subfamily members have been found to possess a conserved 34-amino-acid motif called ALP-like motif [10]

ALP (PDLIM3: PDZ and LIM domain protein 3) is the 39 kDa, 364 amino-acid protein present in heart and skeletal muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [8]. Apart from the PDZ domain, ALP possess an two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2.

Mystique protein, also referred to as PDLIM2, is the most recent member with ~37.5 kDa, 352 amino-acid human protein [11]. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[9].

RIL protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[10].

hCLIM1 also referred to as PDLIM1, is the human orthologue of rat CLP36, the first member of the ALP subfamily. At 36 kDa and 329 amino acids, splice isoform of this protein is yet unidentified (UniProtKB ID:O00151 [11].






Function and Interactions

All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk; an elegant summary of the molecular interactions and plausible functions of ALP, Mystique, RIL, and hCLIM1 can be found in [12] and [13].

Pathology

Known pathology within the ALP subfamily, resulting from mutation and genetic studies have been documented in [14] and [15].

References

  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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  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. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  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
  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. ↑ 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
  15. ↑ 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
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