β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins

Sijo Mathew, Zhenwei Lu, Riya J. Palamuttam, Glenda Mernaugh, Arina Hadziselimovic, Jiang Chen, Nada Bulus, Leslie S. Gewin, Markus Voehler, Alexander Meves, Christoph Ballestrem, Reinhard Fässler, Ambra Pozzi, Charles R. Sanders, Roy Zent

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 mutat ions 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 β 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.

Original languageEnglish (US)
Pages (from-to)4080-4091
Number of pages12
JournalMolecular and Cellular Biology
Volume32
Issue number20
DOIs
StatePublished - Oct 1 2012

Fingerprint

Collecting Kidney Tubules
Integrins
Tail
Talin
Maintenance
Kidney
Proteins
Phenylalanine
Alanine
Mutation
Tyrosine
Carrier Proteins
Magnetic Resonance Spectroscopy
Membranes
Ions
Phenotype
Wounds and Injuries

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins. / Mathew, Sijo; Lu, Zhenwei; Palamuttam, Riya J.; Mernaugh, Glenda; Hadziselimovic, Arina; Chen, Jiang; Bulus, Nada; Gewin, Leslie S.; Voehler, Markus; Meves, Alexander; Ballestrem, Christoph; Fässler, Reinhard; Pozzi, Ambra; Sanders, Charles R.; Zent, Roy.

In: Molecular and Cellular Biology, Vol. 32, No. 20, 01.10.2012, p. 4080-4091.

Research output: Contribution to journalArticle

Mathew, S, Lu, Z, Palamuttam, RJ, Mernaugh, G, Hadziselimovic, A, Chen, J, Bulus, N, Gewin, LS, Voehler, M, Meves, A, Ballestrem, C, Fässler, R, Pozzi, A, Sanders, CR & Zent, R 2012, 'β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins', Molecular and Cellular Biology, vol. 32, no. 20, pp. 4080-4091. https://doi.org/10.1128/MCB.00568-12
Mathew, Sijo ; Lu, Zhenwei ; Palamuttam, Riya J. ; Mernaugh, Glenda ; Hadziselimovic, Arina ; Chen, Jiang ; Bulus, Nada ; Gewin, Leslie S. ; Voehler, Markus ; Meves, Alexander ; Ballestrem, Christoph ; Fässler, Reinhard ; Pozzi, Ambra ; Sanders, Charles R. ; Zent, Roy. / β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 20. pp. 4080-4091.
@article{ed512c2ccd074c7abe1693e34c36dbab,
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 mutat ions 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 β 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.",
author = "Sijo Mathew and Zhenwei Lu and Palamuttam, {Riya J.} and Glenda Mernaugh and Arina Hadziselimovic and Jiang Chen and Nada Bulus and Gewin, {Leslie S.} and Markus Voehler and Alexander Meves and Christoph Ballestrem and Reinhard F{\"a}ssler and Ambra Pozzi and Sanders, {Charles R.} and Roy Zent",
year = "2012",
month = "10",
day = "1",
doi = "10.1128/MCB.00568-12",
language = "English (US)",
volume = "32",
pages = "4080--4091",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "20",

}

TY - JOUR

T1 - β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins

AU - Mathew, Sijo

AU - Lu, Zhenwei

AU - Palamuttam, Riya J.

AU - Mernaugh, Glenda

AU - Hadziselimovic, Arina

AU - Chen, Jiang

AU - Bulus, Nada

AU - Gewin, Leslie S.

AU - Voehler, Markus

AU - Meves, Alexander

AU - Ballestrem, Christoph

AU - Fässler, Reinhard

AU - Pozzi, Ambra

AU - Sanders, Charles R.

AU - Zent, Roy

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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 mutat ions 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 β 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.

AB - 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 mutat ions 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 β 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.

UR - http://www.scopus.com/inward/record.url?scp=84868676221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868676221&partnerID=8YFLogxK

U2 - 10.1128/MCB.00568-12

DO - 10.1128/MCB.00568-12

M3 - Article

C2 - 22869523

AN - SCOPUS:84868676221

VL - 32

SP - 4080

EP - 4091

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 20

ER -