Alpha-7 integrin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''ITGA7''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in

cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

and

smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

cells, and localizes to

Z-disc A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called musc ...

and

costamere The costamere is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane (i.e. the sarcolemma).20: 2327-2331 Costameres are sub-sarcolemmal protein assemblies circumferentially a ...

structures. Mutations in ''ITGA7'' have been associated with congenital myopathies and

noncompaction cardiomyopathy Noncompaction cardiomyopathy (NCC) is a rare congenital disease of heart muscle that affects both children and adults. It results from abnormal prenatal development of heart muscle. During development, the majority of the heart muscle is a sp ...

, and altered expression levels of alpha-7 integrin have been identified in various forms of

muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...

Structure

''ITGA7'' encodes the

alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s in length.

Integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

s are heterodimeric

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...

s composed of an alpha chain and a beta chain. Alpha-7 integrin undergoes post-translational cleavage within the

extracellular domain An ectodomain is the Protein domain, domain of a Cell membrane, membrane protein that extends into the extracellular space (the space outside a cell (biology), cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces ...

to yield disulfide-linked light and heavy chains that join with beta 1 to form an

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

that binds to the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

laminin-1. The primary binding partners of alpha-7 integrin are laminin-1 ( alpha1- beta1- gamma1), laminin-2 ( alpha2- beta1- gamma1) and laminin-4 ( alpha2- beta2- gamma1). Alpha-7/ beta-1 is the major

complex expressed in differentiated muscle cells. Splice variants of alpha-7 integrin that differ in both the

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

and

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

ic domains exist in the mouse and are developmentally regulated in mouse and rat muscle tissue. The X1/X2

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

region lies in the

and alters the ligand binding site; specifically, the conserved homology repeat domains 3 and 4. The first identified human transcript contains

and

ic domains corresponding to the mouse X2 and B variants, respectively. A unique extracellular

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

was also identified in human. The differentially spliced

variants Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...

detected in rodents have also been detected in humans. Major

ic, developmentally regulated variants, alpha-7A and alpha-7B, as well as

, X1 and X2 were identified in humans. Moreover, the D

variant Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...

, but not the C

was detected in humans. Alpha-7 integrin is highly expressed in

striated muscle Striations means a series of ridges, furrows or linear marks, and is used in several ways: * Glacial striation * Striation (fatigue), in material * Striation (geology), a ''striation'' as a result of a geological fault * Striation Valley, in Ant ...

, namely

skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...

and

, and functions as the major

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

-binding integrin. It was later shown that alpha-7 integrin is also highly expressed in

. The two major

s of alpha-7 integrin appear to have developmentally regulated expression; alpha-7A integrin is expressed solely in

, however alpha-7B integrin is expressed more loosely in

as well as the vasculature.

Function

The function of alpha-7 integrin, as is the case for most

s is to mediate cell membrane interactions with

. The alpha-7/beta-1 integrin complex clearly plays a role in the development of

and

. Alpha-7/beta-1 integrin promotes the adhesion and motility of

myoblast Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development of ...

s, and is likely important in the recruitment of myogenic precursors during muscle differentiation. It was shown however that beta-1D integrin appears at embryonic day 11 and alpha-7 integrin does not appear until embryonic day 17; thus, beta-1D associates with alternate alpha subunits ( alpha-5, alpha-6A) prior to alpha-7. In human

, alpha-7 integrin is also developmentally regulated, being first detected at age 2. In adult

cells, alpha-7 integrin (complexed to beta-1 integrin) is localized to

s and

structures, bound to the four and one half

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 ...

proteins,

FHL1 Four and a half LIM domains protein 1 is a protein that in humans is encoded by the ''FHL1'' gene. Structure LIM proteins, named for 'LIN11, ISL1, and MEC3,' are defined by the possession of a highly conserved double zinc finger motif called t ...

and

FHL2 Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the ''FHL2'' gene. LIM proteins contain a highly conserved double zinc finger motif called the LIM domain. Function FHL-2 is thought to have ...

. It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in

cells; however, the functional significance of this modification has not been investigated. Insights into the function of alpha-7 integrin have come from studies employing mouse transgenesis. A mouse expressing a null allele of the ''ITGA7''

are viable, suggesting that alpha-7 integrin is not essential for normal

myogenesis Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development o ...

; however, these mice develop a phenotype that resembles

. In soleus muscle, there was a significant disruption of

myotendinous junction Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...

s, variation in the size of fibers, centrally located nuclei,

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

, and elevated serum levels of

creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...

. It has also been proposed that alpha-7 integrin and gamma-sarcoglycan have overlapping functions in

. In support of this, a double knockout of gamma-sarcoglycan and alpha-7 integrin produced a phenotype that was far worse than either knockout alone. Mice died within 1 month of birth and had severe muscle degeneration, suggesting that the roles of these proteins may overlap to maintain the stability of the

sarcolemma The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte. It consists of a lipid bilayer and a thin oute ...

. Moreover, the double knockout of

dystrophin Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costa ...

and alpha-7 integrin produced a

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...

-like phenotype, and demonstrated that alterations in alpha-7 integrin affect the pathological changes observed in

deficiencies. In support of this notion, AAV overexpression of ''ITGA7'' in

of Duchenne muscular dystrophy (DMD) mice showed a significant protective effect against adverse functional parameters associated with DMD, combined with a reversal of these negative features, suggesting that alpha-7 integrin may be a potential therapeutic candidate to treat

. Studies employing mutant alpha-7 integrin constructs have shown that the

ic tail of alpha-7B integrin is essential for regulation of

lamellipodia The lamellipodium (plural lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional ...

formation and regulation of cell mobility regulation via laminin-1/E8 and p130(CAS)/ Crk complex formation.

Clinical Significance

Mutations in ''ITGA7'' have been found in patients with unclassified

congenital myopathy Congenital myopathy is a very broad term for any muscle disorder present at birth. This defect primarily affects skeletal muscle fibres and causes muscular weakness and/or hypotonia. Congenital myopathies account for one of the top neuromuscular di ...

. Additionally, in patients with severe congenital fiber type disproportion and left ventricular non-compaction cardiomyopathy, a missense mutation, Glu882 Lys, was identified in ''ITGA7'' along with a missense mutation in ''MYH7B'', both novel disease genes having a synergistic effect on disease severity. Alpha-7B integrin expression has been shown to be significantly decreased at sarcolemmal membranes in patients with laminin alpha2 chain-deficient congenital muscular dystrophy. Additionally, in

and

Becker muscular dystrophy Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes ...

, the expression of alpha-7B integrin was enhanced.

Interactions

ITGA7 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: * Merosin *

ITGB1 Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ''ITGB1'' gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen r ...

and *

FHL3 Four and a half LIM domains protein 3 is a protein that in humans is encoded by the ''FHL3'' gene. LIM proteins are defined by the possession of a highly conserved double zinc finger motif called the LIM domain. upplied by OMIMref name="entrez"/ ...

References

External links

ITGA7
Info with links in th
Cell Migration Gateway
{{Integrins Integrins