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MBC in Press, published online ahead of print June 11, 2004
Mol. Biol. Cell 10.1091/mbc.E04-02-0085

A more recent version of this article appeared on August 1, 2004
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Submitted on February 2, 2004
Revised on May 17, 2004
Accepted on June 2, 2004

Identification of Integrin {beta} Subunit Mutations that Alter Heterodimer Function In Situ

Alison L. Jannuzi, Thomas A. Bunch, Robert F. West, and Danny L. Brower*

Department of Molecular and Cellular Biology, and Department of Biochemistry and Molecular Biophysics, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724

Monitoring Editor: Jean Schwarzbauer

We conducted a genetic screen for mutations in myospheroid, the gene encoding the Drosophila {beta}PS integrin subunit, and identified point mutants in all of the structural domains of the protein. Surprisingly, we find that mutations in very strongly conserved residues will often allow sufficient integrin function to support the development of adult animals, including mutations in the ADMIDAS site and in a cytoplasmic NPXY motif. Many mutations in the I-like domain reduce integrin expression specifically when {beta}PS is combined with activating {alpha}PS2 cytoplasmic mutations, indicating that integrins in the extended conformation are unstable relative to the inactive, bent heterodimers. Interestingly, the screen has identified alleles that show gain-of-function characteristics in cell culture, but have negative effects on animal development or viability. This is illustrated by the allele mysb58; available structural models suggest that the molecular lesion of mysb58, V409>D, should promote the "open" conformation of the {beta} subunit I-like domain. This expectation is supported by the finding that {alpha}PS2{beta}PS (V409>D) promotes adhesion and spreading of S2 cells more effectively than does wild-type {alpha}PS2{beta}PS, even when {beta}PS is paired with {alpha}PS2 containing activating cytoplasmic mutations. Finally, comparisons with the sequence of human {beta}8 suggest that evolution has targeted the "mysb58" residue as a means of affecting integrin activity.

*Corresponding author. E-mail: dbrower{at}email.arizona.edu






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