?1 integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins.

ABSTRACT: Loss of ?1 integrin expression inhibits renal collecting-system development. Two highly conserved NPXY motifs in the distal ?1 tail regulate integrin function by associating with phosphtyrosine binding (PTB) proteins, such as talin and kindlin. Here, we define the roles of these two tyrosines in collecting-system development and delineate the structural determinants of the distal ?1 tail using nuclear magnetic resonance (NMR). Mice carrying alanine mutations have moderate renal collecting-system developmental abnormalities relative to ?1-null mice. Phenylalanine mutations did not affect renal collecting-system development but increased susceptibility to renal injury. NMR spectra in bicelles showed the distal ?1 tail is disordered and does not interact with the model membrane surface. Alanine or phenylalanine mutations did not alter ?1 structure or interactions between ? and ?1 subunit transmembrane/cytoplasmic domains; however, they did decrease talin and kindlin binding. Thus, these studies highlight the fact that the functional roles of the NPXY motifs are organ dependent. Moreover, the ?1 cytoplasmic tail, in the context of the adjacent transmembrane domain in bicelles, is significantly different from the more ordered, membrane-associated ?3 integrin tail. Finally, tyrosine mutations of ?1 NPXY motifs induce phenotypes by disrupting their interactions with critical integrin binding proteins like talins and kindlins.

SUBMITTER: Mathew S 

PROVIDER: S-EPMC3457338 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature