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SUMMARY:Short Talk 8\, Yong Wang - Integrative Ensemble Modeling of a Larg
 e Membrane Protein Complex Using Diverse and Ambiguous Information
DTSTART;VALUE=DATE-TIME:20191010T141000Z
DTEND;VALUE=DATE-TIME:20191010T143000Z
DTSTAMP;VALUE=DATE-TIME:20260526T072136Z
UID:indico-contribution-790@lindico453.srv.lu.se
DESCRIPTION:Speakers: Yong Wang (University of Copenhagen)\nMitochondria c
 ontain approximately 1200 different proteins\, 99% of which are synthesize
 d on cytosolic ribosomes and need to be delivered into the right destinati
 on through the intermembrane space by transport machineries\, such as the 
 TIM chaperone. Currently\, the mechanistic and structural details of how t
 he TIM chaperone binds to these mitochondrial proteins remain elusive. To 
 gain structural insight into the binding and chaperone mechanisms\, we foc
 used on the complex of the TIM9/10 chaperone and the mitochondrial GDP/GTP
  carrier membrane protein (Ggc1). Such complexes are difficult to study be
 cause they consist of a transiently formed\, dynamic complex between two f
 olded proteins and a membrane protein that should be solubilized and bound
  by the chaperone. X-ray crystallography has revealed the core structure o
 f the free chaperone protein\, but because of the dynamic nature and large
  size (~1400 amino acids) of the complex its structural features have rema
 ined elusive. Using an integrative approach that combines biochemical assa
 ys\, NMR spectroscopy and SAXS it was\, however\, able to obtain detailed 
 but ambiguous information on the structures of the complex. In particular\
 , the experiments showed that the complex consists of two well-structured 
 (TIM9)3/(TIM10)3 hexamers bound to a mostly disordered Ggc1. In this work\
 , we developed a protocol to integrate such heterogeneous experimental dat
 a with a coarse-grained molecular model to provide a description of the co
 nformational ensemble of the TIM9/10-Ggc1 complex. In particular\, we used
  a hybrid structure-based model (to describe the intra-molecular interacti
 ons within the folded chaperone)\, an NMR-derived contact potential for ch
 aperone-client interactions and a knowledge-based potential (to describe t
 he inter-molecular interactions between the chaperones and chaperone-clien
 t interactions). We used molecular dynamics (MD) simulations to sample the
  conformational landscape of the complex\, and the resulting coarse-graine
 d conformational ensemble was subsequently converted into all-atom resolut
 ion and refined using a Bayesian/Maximum Entropy re-weighting approach usi
 ng the SAXS data. This allows us to generate a weighted ensemble in agreem
 ent with experimental measurement. Such integrative structural modeling me
 thod is useful to generate a structural ensemble of large and dynamic prot
 eins in a both efficient and reliable way.\n\nReference:\nKatharina Weinh
 äupl\, Caroline Lindau\, Audrey Hessel\, Yong Wang\, Conny Schütze\, To
 bias Jores\,\nLaura Melchionda\, Birgit Schönfisch\, Hubert Kalbacher\, B
 eate Bersch\, Doron Rapaport\, Martha\nBrennich\, Kresten Lindorff-Larsen\
 , Nils Wiedemann* and Paul Schanda*. Structural Basis of\nMembrane Protein
  Chaperoning Through the Mitochondrial Intermembrane Space. Cell\, 175\, 1
 365-\n1379\, (2018)\n\nhttps://lindico453.srv.lu.se/event/125/contribution
 s/790/
LOCATION:Kulturen Auditorium
URL:https://lindico453.srv.lu.se/event/125/contributions/790/
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