TY - JOUR
T1 - Protocadherin cis-dimer architecture and recognition unit diversity
AU - Goodman, Kerry M.
AU - Rubinstein, Rotem
AU - Dan, Hanbin
AU - Bahna, Fabiana
AU - Mannepalli, Seetha
AU - Ahlsén, Göran
AU - Thu, Chan Aye
AU - Sampogna, Rosemary V.
AU - Maniatis, Tom
AU - Honig, Barry
AU - Shapiro, Lawrence
N1 - Publisher Copyright: © 2017, National Academy of Sciences. All rights reserved.
PY - 2017/11/14
Y1 - 2017/11/14
N2 - Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non–self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire of cis-dimers. We describe the structure of a PcdhγB7 cis-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdh cis-dimerization and cell surface transport. The structure explains the known restrictions of cis-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions on cis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.
AB - Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non–self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire of cis-dimers. We describe the structure of a PcdhγB7 cis-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdh cis-dimerization and cell surface transport. The structure explains the known restrictions of cis-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions on cis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.
KW - Clustered protocadherin
KW - Crystal structure
KW - Neuronal self-avoidance
KW - Protein–protein interaction
KW - Self-recognition
UR - http://www.scopus.com/inward/record.url?scp=85033704963&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1713449114
DO - https://doi.org/10.1073/pnas.1713449114
M3 - مقالة
SN - 0027-8424
VL - 114
SP - E9829-E9837
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -