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The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

ABSTRACT: The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete C? model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.

SUBMITTER: Chou HT

PROVIDER: S-EPMC6726506 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

Chou Hui-Ting HT Apelt Luise L Farrell Daniel P DP White Susan Roehl SR Woodsmith Jonathan J Svetlov Vladimir V Goldstein Jaclyn S JS Nager Andrew R AR Li Zixuan Z Muller Jean J Dollfus Hélène H Nudler Evgeny E Stelzl Ulrich U DiMaio Frank F Nachury Maxence V MV Walz Thomas T

Structure (London, England : 1993) 20190711 9

The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help ...[more]

PMID: 31303482

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Project description:BackgroundThis study was performed to identify the non- synonymous polymorphisms in the myosin heavy chain 1 gene (MYH1) association with skeletal muscle development in economically important Jeju Native Pig (JNP) and Berkshire breeds. Herein, we present an in silico analysis, with a focus on (a) in silico approaches to predict the functional effect of non-synonymous SNP (nsSNP) in MYH1 on growth, and (b) molecular docking and dynamic simulation of MYH1 to predict the effects of those nsSNP on protein-protein association.ResultsThe NextGENe (V 2.3.4.) tool was used to identify the variants in MYH1 from JNP and Berkshire using RNA seq. Gene ontology analysis of MYH1 revealed significant association with muscle contraction and muscle organ development. The 95 % confidence intervals clearly indicate that the mRNA expression of MYH1 is significantly higher in the Berkshire longissimus dorsi muscle samples than JNP breed. Concordant in silico analysis of MYH1, the open-source software tools identified 4 potential nsSNP (L884T, K972C, N981G, and Q1285C) in JNP and 1 nsSNP (H973G) in Berkshire pigs. Moreover, protein-protein interactions were studied to investigate the effect of MYH1 mutations on association with hub proteins, and MYH1 was found to be closely associated with the protein myosin light chain, phosphorylatable, fast skeletal muscle MYLPF. The results of molecular docking studies on MYH1 (native and 4 mutants) and MYLFP demonstrated that the native complex showed higher electrostatic energy (-466.5 Kcal mol(-1)), van der Walls energy (-87.3 Kcal mol(-1)), and interaction energy (-835.7 Kcal mol(-1)) than the mutant complexes. Furthermore, the molecular dynamic simulation revealed that the native complex yielded a higher root-mean-square deviation (0.2-0.55 nm) and lower root-mean-square fluctuation (approximately 0.08-0.3 nm) as compared to the mutant complexes.ConclusionsThe results suggest that the variants at L884T, K972C, N981G, and Q1285C in MYH1 in JNP might represent a cause for the poor growth performance for this breed. This study is a pioneering in-depth in silico analysis of polymorphic MYH1 and will serve as a valuable resource for further targeted molecular diagnosis and population-based studies conducted for improving the growth performance of JNP.

Dataset Information

The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

Publications

The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

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