title: Structural insights on the Mycobacterium tuberculosis proteasomal ATPase Mpa.
abstract: Proteasome-mediated protein turnover in all domains of life is an energy-dependent process that requires ATPase activity. Mycobacterium tuberculosis (Mtb) was recently shown to possess a ubiquitin-like proteasome pathway that plays an essential role in Mtb resistance to killing by products of host macrophages. Here we report our structural and biochemical investigation of Mpa, the presumptive Mtb proteasomal ATPase. We demonstrate that Mpa binds to the Mtb proteasome in the presence of ATPgammaS, providing the physical evidence that Mpa is the proteasomal ATPase. X-ray crystallographic determination of the conserved interdomain showed a five stranded double beta barrel structure containing a Greek key motif. Structure and mutational analysis indicate a major role of the interdomain for Mpa hexamerization. Our mutational and functional studies further suggest that the central channel in the Mpa hexamer is involved in protein substrate translocation and degradation. These studies provide insights into how a bacterial proteasomal ATPase interacts with and facilitates protein degradation by the proteasome.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Lin
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tang
authors.forename: Dongyang
authors.initials: D
authors.lastname: Li
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
authors.forename: K Heran
authors.initials: KH
authors.lastname: Darwin
authors.forename: Huilin
authors.initials: H
authors.lastname: Li
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C479920:Mpa protein, Mycobacterium tuberculosis