Kinase Subfamily Unc89

Kinase Classification: Group CAMK: Family MLCK: Subfamily Unc89

The Unc89 subfamily is named after the C. elegans unc-89 kinase, and also includes Drosophila unc-89 and the vertebrate proteins obscurin (obscn) and Speg. They are generally extremely long proteins with arrays of immunoglobulin domains, twin kinase domains and at least one RhoGEF guanine nucleotide exchange factor domain.

Domain Structure

These proteins are typically about 8000 AA long, with a large N-terminal array of immunoglobulin repeats, and dual kinase domains at the C-terminus, which are separated by and Ig and an FN3 domain. Most members contain a RhoGEF domain: in vertebrates, it is just upstream of the kinase domains, in Drosophila and C. elegans it is near or at the N terminus. Vertebrate SPEG is about 3200 AA, with a shorter array of Ig repeats, no RhoGEF, and no FN3 between the kinase domains. All characterized members are extensively alternatively spliced. In human, some OBSCN isoforms also lack the kinase domains [1]. Other short isoforms contain the kinase domains and have been reported as extracellular [2].

Vertebrates also encode OBSL1, a homolog of obscurin consisting of the Ig repeats but lacking the kinase and RhoGEF domains [3]. OBSCN and OBSL1 can bind Titin via specific Ig domains [4].

Functions

Unc89 members function in sarcomere assembly in muscle cells, and appear to have a range of cytoskeletal functions in non-muscle cells.

Classification History

From 2002 to 2010, Unc89 proteins were classified with the Trio subfamily as a distinct family. They have now been merged into the MLCK family, along with the classical MLCKs and Titin. Unc89 and Trio subfamilies share the presence of RhoGEF and PH domains, though their kinase domains are not particularly similar to each other.

References

1. Ackermann MA, Shriver M, Perry NA, Hu LY, and Kontrogianni-Konstantopoulos A. Obscurins: Goliaths and Davids take over non-muscle tissues. PLoS One. 2014;9(2):e88162. DOI:10.1371/journal.pone.0088162 |
2. Hu LY and Kontrogianni-Konstantopoulos A. The kinase domains of obscurin interact with intercellular adhesion proteins. FASEB J. 2013 May;27(5):2001-12. DOI:10.1096/fj.12-221317 |
3. Geisler SB, Robinson D, Hauringa M, Raeker MO, Borisov AB, Westfall MV, and Russell MW. Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to obscurin. Genomics. 2007 Apr;89(4):521-31. DOI:10.1016/j.ygeno.2006.12.004 |
4. Pernigo S, Fukuzawa A, Pandini A, Holt M, Kleinjung J, Gautel M, and Steiner RA. The crystal structure of the human titin:obscurin complex reveals a conserved yet specific muscle M-band zipper module. J Mol Biol. 2015 Feb 27;427(4):718-736. DOI:10.1016/j.jmb.2014.11.019 |