Towards Understanding the Roles of Prohibitins, Multi-Functional Regulator Proteins

Andreas      Hofmann; Anja      Winter

Abstract

Prohibitins comprise a family of highly conserved ubiquitous eukaryotic proteins that localise to different compartments of the cell. They have been implicated in important cellular processes such as cellular signalling and transcriptional control, apoptosis, cellular senescence, early development of Caenorhabditis elegans and mitochondrial biogenesis. In yeast, mammals and C. elegans there exist at least two homologous prohibitin proteins (yeast: PHB1, PHB2; human: BAP32, BAP37), which assemble into high molecular weight complexes of about 1.2 MDa in the inner mitochondrial membrane. Experimentally determined structural information about these proteins has been elusive for a long time. Recently, however, the biogenesis and architecture of the yeast prohibitin complex has been analysed and yielded ringshaped structures as visualised by single particle electron microscopy. Structural details at atomic level remain to be determined, but a first step into this direction is provided by modelling approaches. Prohibitins consist of three domains, an N-terminal transmembrane helix, a middle (PHB) domain and a C-terminal coiled coil domain. The PHB domain is the landmark feature within the super-family of SPFH (stomatin/prohibitin/flotillin/HflK/C) domain proteins. The recently determined NMR structure of mouse flotillin-2 provides a first access to structural details of prohibitins. While the first functional role attributed to prohibitins was the regulation of cellular senescence, DNA transcription and tumour cell growth, there is recent evidence that they also can act as markers for adipose tissue. In a mouse model, an apoptotic peptide targeted at prohibitin was successful in reversing obesity. An extracellular complex containing both BAP32 and BAP37 was found to bind to the Vi capsular polysaccharide, first identified as a virulence antigen of Salmonella typhi, suggesting a key role for both proteins in infection with S. typhi. Furthermore, the interaction of prohibitin with compounds activating melanin production has placed these proteins at a central position in melanogenesis, and further implicates mitochondria in signalling pathways of the pigmentation process. Accumulating evidence suggests that prohibitins are implicated in mitochondrial, age and oxidative stress-related diseases, as well as in immunity and inflammation, cancer and cancer-like diseases, obesity, and drug resistance. The complementary interplay between structural and chemical biology will provide important insights into the molecular mechanisms of prohibitins and, more generally, the functions of mitochondria in living cells. This review discusses the current state of knowledge about prohibitins, and provides a vision for further developments in the field of these eminently important proteins.

Keywords: Molecular modelling, PHB domain, protein-protein interactions, m-AAA-protease, melanogenin

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