title: β1 integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins.
abstract: Loss of β1 integrin expression inhibits renal collecting-system development. Two highly conserved NPXY motifs in the distal β1 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 β1 tail using nuclear magnetic resonance (NMR). Mice carrying alanine mutations have moderate renal collecting-system developmental abnormalities relative to β1-null mice. Phenylalanine mutations did not affect renal collecting-system development but increased susceptibility to renal injury. NMR spectra in bicelles showed the distal β1 tail is disordered and does not interact with the model membrane surface. Alanine or phenylalanine mutations did not alter β1 structure or interactions between α and β1 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 β1 cytoplasmic tail, in the context of the adjacent transmembrane domain in bicelles, is significantly different from the more ordered, membrane-associated β3 integrin tail. Finally, tyrosine mutations of β1 NPXY motifs induce phenotypes by disrupting their interactions with critical integrin binding proteins like talins and kindlins.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Sijo
authors.initials: S
authors.lastname: Mathew
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Lu
authors.forename: Riya J
authors.initials: RJ
authors.lastname: Palamuttam
authors.forename: Glenda
authors.initials: G
authors.lastname: Mernaugh
authors.forename: Arina
authors.initials: A
authors.lastname: Hadziselimovic
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.forename: Nada
authors.initials: N
authors.lastname: Bulus
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Gewin
authors.forename: Markus
authors.initials: M
authors.lastname: Voehler
authors.forename: Alexander
authors.initials: A
authors.lastname: Meves
authors.forename: Christoph
authors.initials: C
authors.lastname: Ballestrem
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Charles R
authors.initials: CR
authors.lastname: Sanders
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000737:chemistry / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000254:growth & development*; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D016608:Talin / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C475301:FERMT1 protein, human; D019012:Integrin beta1; D039661:Integrin beta3; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016608:Talin; D014443:Tyrosine