Integrins are a superfamily of cell adhesion receptors that play a crucial role in mediating cell adhesion to the extracellular matrix (ECM) or other cells. They are present across a wide range of organisms, from single-celled to complex multicellular organisms such as mammals. Integrins are involved not only in cell attachment but also in various processes such as cell migration, proliferation, differentiation, and survival.

Classification and Evolution of Integrins

Integrins are transmembrane αβ heterodimers, consisting of an α subunit and a β subunit. Humans have 18 α subunits and 8 β subunits, which combine to form 24 different heterodimers. This combination allows for diversity and specificity in different cell types, tissues, and organisms.

The genomic and evolutionary history of integrins shows that the genes of integrin family members have evolved through gene duplications. Studies indicate that integrin α and β subunits are significantly different from each other. Within each family, the α subunits share about 30% of sequence identity, while β subunits share about 45%. This gene duplication and evolution have maintained and diversified the integrin family across different organisms.

In mammals, integrin α and β subunit genes are located on different chromosomes. For example, integrin subunits expressed in leukocytes (αL, αM, αD, and αX) are clustered in the 16p11 region, while those expressed in platelets and endothelial cells (αIIb and β3) are located at 17q21.32. Genes for α6, α4, and αV are clustered in the 2q31 region. Notably, some integrin α subunits (such as α1, α2, α10, α11, αM, αL, αD, and αX) contain an I (inserted or interacting) domain, while others do not. I domain-containing integrin α subunits are closely related and differ in RGD (Arg-Gly-Asp) motif recognition compared to non-I domain α subunits.

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Structural Features of Integrins

Integrins exhibit complex structural features. The crystal structures of human integrin αVβ3 and αIIbβ3 reveal that the extracellular portion of integrin heterodimers consists of several structural domains. The head of αVβ3 includes a β-propeller domain and a PSI (plexin-semaphorin-integrin) domain, which form the ligand-binding site. The β-propeller domain contains seven repeating units of approximately 60 amino acids each, folding into a seven-blade propeller structure similar to the β subunit of heterotrimeric G proteins.

The I domain contains a metal ion-dependent adhesion site (MIDAS), while the I-like domain has a structurally similar metal-binding motif. The RGD-binding site is located at the interface between the β-propeller domain and the β I-like domain, with amino acid residues directly interacting with the RGD peptide of the ligand. Mutagenesis studies have identified many amino acid residues critical for ligand binding, which, although not contiguous in primary structure, are exposed on the surface of the head to form the ligand-binding surface. Integrins undergo conformational changes upon ligand binding, including displacement of the disulfide-bonded loop structures in the β I-like domain and downward movement of α-helix 7.

Figure 1. Mechanisms of integrin activation. (Aiyelabegan HT, et al., 2017)

Functions and Distribution of Integrins

Integrins serve as traction receptors, enabling cells to sense and respond to mechanical forces applied to the extracellular matrix. In mammals, some integrins are expressed specifically in certain cell types or tissues. For example, αIIbβ3 is expressed only in platelets, α6β4 in keratinocytes, αEβ7 in mucosal tissues' T cells, dendritic cells, and mast cells, α4β1 in leukocytes, α4β7 in some memory T cells, and β2 integrins predominantly in leukocytes. Other integrins like αVβ3 are widely distributed in endothelial cells.

In terms of ligand specificity, mammalian integrins can be broadly categorized into those that bind laminin (e.g., α1β1, α2β1, α3β1, α6β1, α7β1, and α6β4), those that bind collagen (e.g., α1β1, α2β1, α3β1, α10β1, and α11β1), leukocyte integrins (e.g., αLβ2, αMβ2, αXβ2, and αDβ2), and those that recognize the RGD motif (e.g., α5β1, αVβ1, αVβ3, αVβ5, αVβ6, αVβ8, and αIIbβ3). Each integrin has unique ligand specificity. For instance, the tri-peptide LDV on VCAM-1 is recognized by α4β1, and this ligand recognition pattern is conserved across most mammals.

Role of Integrins in Cellular Signaling

By binding extracellular ligands, integrins generate internal signals that influence various cellular behaviors, including migration, proliferation, and survival. Integrins can also receive signals from within the cell, which can regulate the ligand-binding affinity of integrins.

The cytoplasmic tails of integrins are shorter than 75 amino acids (except for the β4 subunit, which has a tail approximately 1000 amino acids long and includes four fibronectin III repeats). The β subunit tails have significant homology, while the α subunit tails are highly divergent, but include a conserved GFFKR motif adjacent to the transmembrane region, crucial for interaction with the β tail. Many cytoskeletal and signaling proteins bind to the cytoplasmic tails of β subunits, with some also interacting with specific α tails. Most integrin β tails contain one or two NPxY/F motifs, which are classic recognition sequences for phosphotyrosine-binding (PTB) domains. The phosphorylation of tyrosine (Y) in the NPxY/F motif may represent a mechanism for regulating the interaction of integrins with other proteins on the cytoplasmic side of the cell membrane. The cytoplasmic tails of integrins also recruit various proteins, such as talin, which bind to actin filaments, forming essential connections with the cytoskeleton for many integrin-mediated functions.

Role of Integrins in Disease

Integrins play significant roles in various diseases. For instance, in cancer, integrins influence tumor growth and metastasis by regulating cell attachment, migration, and invasiveness. In inflammatory diseases, integrins are crucial for the adhesion and migration of leukocytes, affecting the progression of inflammation. Abnormal expression or function of integrins in autoimmune and hematological diseases can also lead to disease development or exacerbation.

Integrins are potential targets for drug development. For example, integrin inhibitors have been developed for treating cancer and inflammatory diseases. These drugs work by blocking the interaction between integrins and their ligands, thereby inhibiting disease progression.

The integrin family, as a superfamily of cell adhesion receptors, exhibits complex structures and functions. Through interactions with extracellular matrix and cell surface ligands, integrins regulate various biological processes such as attachment, migration, proliferation, and survival. The structural characteristics and functions of integrins are conserved across different organisms but also show rich diversity. In-depth research on integrins not only helps to uncover fundamental mechanisms of cell biology but also aids in the development of new therapeutic strategies to address various disease challenges.