PDLIM3

Actin-associated LIM protein (ALP), also known as PDZ and LIM domain protein 3 is a is_associated_with::protein that in humans is encoded by the PDLIM3 is_associated_with::gene. ALP is highly expressed in cardiac and is_associated_with::skeletal muscle, where it localizes to Z-discs and is_associated_with::intercalated discs. ALP functions to enhance the crosslinking of is_associated_with::actin by alpha actinin-2 and also appears to be essential for right ventricular chamber formation and contractile function.

Structure
ALP exists primarily as two alternatively spliced variants; a 39.2 kDa (364 amino acids) is_associated_with::protein in is_associated_with::skeletal muscle and a 34.3 kDa (316 amino acids) is_associated_with::protein in is_associated_with::cardiac muscle and is_associated_with::smooth muscle. ALP has a N-terminal PDZ domain and a C-terminal is_associated_with::LIM domain. In addition, the ALP subfamily contains a specific 34 is_associated_with::amino acid domain named the ALP-like motif, containing is_associated_with::protein kinase C consensus sequences. The is_associated_with::PDZ domain of ALP binds to alpha actinin-2, specifically to its spectrin-like repeats. The is_associated_with::PDZ domain is a motif composed of 80-120 amino acids with conserved four residue GLGF sequences that typically interact with C-termini of cytoskeletal proteins. The region of heterogeneity in the two isoforms is between the is_associated_with::PDZ domain and is_associated_with::LIM domain. ALP is localized to chromosome 4q35. It has been shown that deletion of muscleblind-like 1 in mice can alter the splicing pattern of PDLIM3.

Function
Studies have shown that ALP is present at the first stage of myofibrilogenesis where it is bound to alpha actinin-2, and this association remains intact in mature is_associated_with::myofibrils where ALP is localized to Z-discs and is_associated_with::intercalated discs. Alpha actinin-2 is however not required for targeting ALP to Z-lines. Studies in ALP knockout mice have shown that ALP facilitates the cross-linking of is_associated_with::actin filaments by alpha actinin-2, and absence of ALP induces abnormal right ventricular chamber formation, is_associated_with::dysplasia and is_associated_with::cardiomyopathy. Futher studies using right ventricular epicardial systolic strain and geometric remodeling analysis in these animals unveiled that absence of ALP diminishes right ventricular contractile function and alters the pattern of cardiac hypertrophic remodeling. Interestingly, two studies using integrative genomic approaches to investigate genetic modifiers of collagen deposition or intrinsic aerobic running capactiy (ARC) have mapped PDLIM3 to respective is_associated_with::quantitative trait loci, suggesting that ALP may be involved in molecular networks related to these cardiac phenomena.

Clinical significance
Chromosome 4 pericentric inversion has been observed in 10 patients, with associated cardiac defects linked to terminal 4q35.1 deletions, which may affect PDLIM3.

Interactions
ALP interacts with:
 * alpha actinin-2
 * beta-catenin