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Vol. 15, Issue 8, 3829-3840, August 2004

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Identification of Integrin Subunit Mutations that Alter Heterodimer Function In Situ

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

Submitted February 2, 2004; Revised May 17, 2004; Accepted June 2, 2004
Monitoring Editor: Jean Schwarzbauer

We conducted a genetic screen for mutations in myospheroid, the gene encoding the Drosophila 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 PS is combined with activating 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 mys^b58; available structural models suggest that the molecular lesion of mys^b58, V409>D, should promote the "open" conformation of the subunit I-like domain. This expectation is supported by the finding that PS2PS (V409>D) promotes adhesion and spreading of S2 cells more effectively than does wild-type PS2PS, even when PS is paired with PS2 containing activating cytoplasmic mutations. Finally, comparisons with the sequence of human 8 suggest that evolution has targeted the "mys^b58" residue as a means of affecting integrin activity.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

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

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