Alternative titles; symbolsCLPHGNC Approved Gene Symbol: COTL1Cytogenetic location: 16q24.1 Genomic coordinates (GRCh38): 16:84,565,595-84,618,077 (from NCBI...
Alternative titles; symbols
HGNC Approved Gene Symbol: COTL1
Cytogenetic location: 16q24.1 Genomic coordinates (GRCh38): 16:84,565,595-84,618,077 (from NCBI)
The actin cytoskeleton is regulated by numerous actin-binding proteins, including coactosin, a protein first identified in slime mold. CLP interacts with 5-lipoxygenase (5LO, or ALOX5; 152390), a 78-kD protein expressed in different types of leukocytes, including dendritic cells, that is the first committed enzyme in leukotriene biosynthesis (Provost et al., 1999).
▼ Cloning and Expression
By analysis of cosmids from the region flanking the Smith-Magenis syndrome (SMS; 182290) deletion on chromosome 17, followed by probing of a placenta cDNA library, Chen et al. (1997) obtained a cDNA encoding CLP. The deduced 142-amino acid protein is 75% similar to coactosin. Northern blot analysis detected a 2.0-kb transcript in placenta, liver, lung, and kidney.
Using a yeast 2-hybrid screen of a lung cDNA library with 5LO as bait, Provost et al. (1999) isolated cDNAs encoding CLP. Immunoblot analysis showed expression of a 16-kD protein, in agreement with the predicted size.
Doucet et al. (2002) cloned mouse Clp, which is 95% identical to human CLP.
By Northern blot analysis, Provost et al. (2001) showed that the 2.0-kb CLP transcript is expressed predominantly in placenta, lung, and kidney, with lower levels in brain, liver, and pancreas. In heart, they detected an additional band of 1.4 kb. In immune tissues, highest expression of CLP was in peripheral blood leukocytes, with lower levels in spleen and lymph node. Western blot analysis detected CLP expression in the nonnuclear fraction of neutrophils.
▼ Gene Function
By yeast 2-hybrid analysis, Provost et al. (2001) showed that CLP interacts with F-actin (see 102610) and only transiently interacts with monomeric G-actin. Immunofluorescence microscopy demonstrated colocalization of CLP with F-actin stress fibers in a calcium-independent manner. Mutation analysis established that lys75, but not lys130 and lys131, is critical for the CLP interaction with actin. Lys131 had been shown by Provost et al. (2001) to be responsible for binding of CLP to 5LO.
Doucet et al. (2002) showed that mouse Clp binds 5LO at high salt concentrations and F-actin at low salt concentrations in a pH-sensitive and calcium-independent manner.
Using HPLC analysis, Rakonjac et al. (2006) showed that CLP could serve as a scaffold for Ca(2+)-induced 5LO activity, similar to membranes. In the presence of phosphatidylcholine (membrane), CLP induced increased formation of LTA4 by 5LO. CLP also increased the ratio of 5-HETE to 5-HPETE. Mutation analysis showed that these effects required trp13, trp75, and trp102 in the ligand-binding loops of the 5LO beta sandwich. Western blot analysis showed that stimulation of polymorphonuclear cells with Ca(2+) ionophore induced translocation of CLP and 5LO from the cytosol to the nucleus. Rakonjac et al. (2006) concluded that CLP is relevant to the formation of 5LO products such as 5-HETE in the cytosol of various cell types and, acting in a complex together with 5LO and membranes, increases the capacity of 5LO for leukotriene biosynthesis.
Chen et al. (1997) localized the CLP gene to each end of the SMS deletion region on chromosome 17p11.2 by radiation hybrid and Southern blot analyses. They noted homologous sequences on chromosomes 15, 16, and Y.
However, Gross (2011) mapped the COTL1 gene to chromosome 16q24.1 based on an alignment of the COTL1 sequence (GenBank BC010039) with the genomic sequence (GRCh37).