Molecular modeling of prohibitin domains.
Prohibitins comprise a family of highly conserved ubiquitous eukaryotic proteins that mainly localize to the mitochondria. They have been implicated in important cellular processes such as cellular signaling and transcriptional control, apoptosis, cellular senescence, and mitochondrial biogenesis. Using molecular modeling techniques, we have generated structural models of human prohibitins BAP32 and BAP37, which have previously been shown to exist as large ringlike oligomers in the membrane-bound state. The middle domain of prohibitins is evolutionary conserved in the family of SPFH (PHB) domain proteins. On the basis of the known structure of flotillin-2, another member of the SPFH-domain family, we have generated homology models for BAP32 and BAP37, and elucidated the implications for formation of high molecular weight oligomers. A model for the dimeric-building block of BAP32: BAP37 for such assemblies was generated and its stability scrutinized by molecular dynamics simulations. The model of BAP32 was also analyzed as to potential ligand-binding sites and the previously identified ligand melanogenin was docked into a membrane-proximal cavity. The results are discussed in the context of prohibitin interactions with mitochondrial AAA-proteases and we suggest two possible interaction interfaces between the BAP32:BAP37 building block and the protease.
Winter
Anja
A
Institute of Structural and Molecular Biology, School of Biological Sciences, The University of Edinburgh, Scotland, United Kingdom.
Kämäräinen
Outi
O
Hofmann
Andreas
A
D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D000091402:Prohibitins; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017385:Sequence Homology
C000717328:PHB protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D010447:Peptide Hydrolases