6MER

PcdhgB3 EC1-4 in 50 mM HEPES

6MER の概要

• エントリーDOI: 10.2210/pdb6mer/pdb
• 分子名称: Protocadherin gamma-B3, CALCIUM ION (3 entities in total)
• 機能のキーワード: cell-adhesion, neuronal self-avoidance, cell adhesion
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46302.91

構造登録者

Nicoludis, J.M.,Gaudet, R. (登録日: 2018-09-06, 公開日: 2019-09-04, 最終更新日: 2024-11-06)

主引用文献

Nicoludis, J.M.,Green, A.G.,Walujkar, S.,May, E.J.,Sotomayor, M.,Marks, D.S.,Gaudet, R.
Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis.
Proc.Natl.Acad.Sci.USA, 116:17825-17830, 2019

PubMed Abstract: Clustered protocadherins, a large family of paralogous proteins that play important roles in neuronal development, provide an important case study of interaction specificity in a large eukaryotic protein family. A mammalian genome has more than 50 clustered protocadherin isoforms, which have remarkable homophilic specificity for interactions between cellular surfaces. A large antiparallel dimer interface formed by the first 4 extracellular cadherin (EC) domains controls this interaction. To understand how specificity is achieved between the numerous paralogs, we used a combination of structural and computational approaches. Molecular dynamics simulations revealed that individual EC interactions are weak and undergo binding and unbinding events, but together they form a stable complex through polyvalency. Strongly evolutionarily coupled residue pairs interacted more frequently in our simulations, suggesting that sequence coevolution can inform the frequency of interaction and biochemical nature of a residue interaction. With these simulations and sequence coevolution, we generated a statistical model of interaction energy for the clustered protocadherin family that measures the contributions of all amino acid pairs at the interface. Our interaction energy model assesses specificity for all possible pairs of isoforms, recapitulating known pairings and predicting the effects of experimental changes in isoform specificity that are consistent with literature results. Our results show that sequence coevolution can be used to understand specificity determinants in a protein family and prioritize interface amino acid substitutions to reprogram specific protein-protein interactions.

PubMed: 31431536
DOI: 10.1073/pnas.1821063116

実験手法

X-RAY DIFFRACTION (3 Å)