Integrins a-subunit

Hickstein, D. D., Hickey, M. J., Ozols, J., Baker, D. M., Back, A. L., Roth, G. J. (1989). cDNA sequence for the aM subunit of the human neutrophil adherence receptor indicates homology to integrin a subunits. Proc. Natl. Acad. Sci. USA 86, 257-61. 

The VWA domains in some integrin a subunits are readily apparent from their sequences. Although much functional evidence (reviewed in Loftus and Liddington, 1997) supports a hypothesis that integrin (3 subunits also contain a VWA domain (Lee et al., 1995 Bajt and Loftus, 1994 Tozer et al., 1996 Tuckwell and Humphries, 1997), there has been no statistical evidence for significant sequence similarity. 

All integrin (3 subunits and half of integrin a subunits contain von Willebrand factor-type A domains of about 200 amino acids, also referred to as the inserted (I) domain in the a-subunit and the I-like domain in the / subunit, respectively (Figs. 1, 2) (Humphries, 2000 Shimaoka et al,... 

Springer, T. A. (1997). Folding of the N-terminal, ligand-binding region of integrin a-subunits into a /1-propeller domain. Proc. Natl. Acad. Sd. USA 94, 65-72. 

The primary structure of GPIa was established by Takada and Hemler ". An overall sequence homology of 18-25% with other integrin a-subunits has been observed. The GPIa sequence contained a similar distribution of cysteine residues, divalent cation metal binding domains and a transmembrane domain . 

Ihckwell DS, Hunqihies Ml, Brass A A secondary structure model of the integrin a subunit N-terminal domain based on analysis of multiple alignments. Cell Adhesion Common 2 385-402,1994. 

Hierck, B.P., Thorsteinsdottir, S., Niessen, C.M., Freund, E., Iperen, L.V., Feyen, A., Hogervorst, F., Poelmann, R.E., Mummery, C.L., and Sonnenberg, A. (1993). Variants of the a P, laminin receptor in early murine development distribution, molecular cloning and chromosomal localization of the mouse integrin a, subunit [published erratum appears in Cell Adhes. Commun. (1993, Sept.) 7f2) following 190]. Cell Adhes Commun. 7 33-53. 

The N-terminal region of the integrin a-subunit contains seven repeats of about 60 amino acids, which fold into a seven-bladed yS-propeller domain (Springer, 1997 Xiong et al, 2001) (Fig. 2A). A yS-propeller domain with the same topology is also found in the trimeric G-protein yS-subunit. The... 

Three subfamilies of integrins were recognized initially. Members of each subfamily were distinguished by containing a common (3 subunit, but they differed in their a subunits. However, more than three P subunits have now been identified, and the classification of integrins has become rather complex. Some integrins of specific interest with regard to neutrophils are fisted in Table 52-11. 

The structure of the integrin family has been deduced largely from the cDNA sequences of the cloned genes. All integrins comprise a- and fl-subunits, and the ligand binding that occurs at the binding site comprises an interaction between the two subunits. The a-subunits can combine with dif-... 

Figure 3.6. Structure of leukocyte integrins. These molecules possess a common -subunit (CD 18) but distinct a-subunits.

However, the PSI-BLAST search method, using a very conservative inclusion threshold of E < 10 4, can detect, with significance, the similarities in sequence between previously known VWA domains and integrin /3 subunits (Table II). The hypothesis that all integrin [3 subunits contain a VWA domain appears to be correct. 

Koster, J., van Wilpe, S., Kuikman, I., Litjens, S. H., and Sonnenberg, A. (2004b). Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Mol. Biol. Cell 15, 1211-1223. 

Yamamoto, H., Irie, A., Fukushima, Y., Ohnishi, T., Arita, N., Hayakawa, T. and Sekiguchi, K. (1996) Abrogation of lung metastasis of human fibrosarcoma cells by ribozymemediated suppression of integrin alpha6 subunit expression. Int. J. Cancer, 65, 519-524. 

Integrins. The integrin family has been identified as excellent candidates for the development of target specific cancer therapies.29 Integrins are heterodimeric glycoproteins that consist of a and P subunits, which combine to form the various types of integrins. Currently, 18 a subunits, 8 P subunits, and approximately 22 different integrins have been identified.29,30... 

Integrins are a family of transmembrane heterodimeric glycoproteins that are receptors for specific epitopes of extracellular matrix proteins and for other cell-surface molecules (Kramer et al, 1993). Integrins exist as a dimer complex composed of an a-subunit (120-180 kD) noncovalently associated with a /1-subunit (90-110 kD) (Hynes, 1992). At least 8 /1-subunits and 14 -units have been identified and are concentrated at loci, called focal adhesion sites, of close proximity between cells and extracellular matrices on substrates (Hynes, 1992). Focal adhesion sites are points of aggregation of, and are physically associated with, intracellular cytoskeletal molecules that control, direct, and modulate cell function in response to extracellular signals (Schwartz, 1992). 

Fig. 1. Integrin a- and /5-subunits form 24 heterodimers that recognize distinct but overlapping ligands. Half of the a subunits contain I domains (asterisks).

Fig. 2. Integrin architecture. (A) Organization of domains within the primary structure. Some a subunits contain an I domain inserted in the position denoted by the dotted lines. Cysteines and disulfide bonds are shown as lines below the stick figures. Red and blue asterisks denote and Mg " " binding sites, respectively.

The j3 subunit I-like domain, which is inserted in the hybrid domain of the /3-subunit (Fig. 2A), directly binds ligand in integrins that lack I domains in the a subunit (Fig. 3C, Fig. 6A). By contrast, when the I... 

Aumailley, M., Timpl, R., and Sonnenberg, A. (1990). Antibody to integrin a6 subunit specifically inhibits cell-binding to laminin fragment 8. Exper. Cell Res. 188, 55-60. 

Huang, C., Zang, Q., Takagi, J., and Springer, T. A. (2000). Structural and functional studies with antibodies to the integrin /32 subunit A model for the I-like domain. J. Biol. Chem. 275, 21514-21524. 

---