Actin-associated LIM protein (ALP), also known as PDZ and LIM domain protein 3 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''PDLIM3''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. ALP is highly expressed in

cardiac The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrients to the tissu ...

and

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

, where it localizes to Z-discs and

intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...

s. ALP functions to enhance the crosslinking of

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...

by alpha-actinin-2 and also appears to be essential for

right ventricular A ventricle is one of two large chambers located toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in t ...

chamber formation and contractile function.

Structure

ALP exists primarily as two alternatively spliced variants; a 39.2 kDa (364 amino acids)

and a 34.3 kDa (316 amino acids)

cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...

and

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

. ALP has a

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

PDZ domain and a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

LIM domain LIM domains are protein structural domains, composed of two contiguous zinc fingers, separated by a two-amino acid residue hydrophobic linker. The domain name is an acronym of the three genes in which it was first identified (LIN-11, Isl-1 and M ...

. In addition, the ALP subfamily contains a specific 34

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

domain named the ALP-like motif, containing

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

consensus sequences. The

PDZ domain The PDZ domain is a common structural domain of 80-90 Amino acid, amino-acids found in the Signal transduction, signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring recept ...

of ALP binds to alpha actinin-2, specifically to its spectrin-like repeats. The

is a motif composed of 80-120 amino acids with conserved four residue GLGF sequences that typically interact with

C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When ...

of cytoskeletal proteins. The region of heterogeneity in the two isoforms is between the

and

. 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

myofibrils A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibr ...

where ALP is localized to Z-discs and

s. 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

filaments by alpha actinin-2, and absence of ALP induces abnormal

chamber formation,

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...

and

cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

. Further studies using

epicardial The pericardium (: pericardia), also called pericardial sac, is a double-walled sac containing the heart and the roots of the great vessels. It has two layers, an outer layer made of strong inelastic connective tissue (fibrous pericardium), a ...

systolic strain and geometric remodeling analysis in these animals unveiled that absence of ALP diminishes

contractile function and alters the pattern of cardiac hypertrophic remodeling. Two studies using integrative genomic approaches to investigate genetic modifiers of collagen deposition or intrinsic aerobic running capacity (ARC) have mapped ''PDLIM3'' to respective

quantitative trait loci A quantitative trait locus (QTL) is a Locus (genetics), locus (section of DNA) that correlates with variation of a quantitative trait in the phenotype of a Population genetics, population of organisms. QTLs are mapped by identifying which molecula ...

, 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 Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...

Structure

Function

Clinical significance

Interactions

References

Further reading