Biomedical subjects

Louise C Briggs

Publications and source records attributed to Louise C Briggs.

3 recordsLinked to original sources

PubMed2006

Conformational changes in the AAA ATPase p97-p47 adaptor complex.

The AAA+ATPase p97/VCP, helped by adaptor proteins, exerts its essential role in cellular events such as endoplasmic reticulum-associated protein degradation or the reassembly of Golgi, ER and the nuclear envelope after mitosis. Here, we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer, one of the major p97 adaptor proteins involved in membrane fusion. Depending on the nucleotide state, we observe the p47 trimer to be in two distinct arrangements on top of the p97 hexamer. By combining the EM data with NMR and other biophysical measurements, we propose a model of ATP-dependent p97(N) domain motions that lead to a rearrangement of p47 domains, which could result in the disassembly of target protein complexes.

Adenosine Triphosphatases↗

PubMed2006

Going through the motions: the ATPase cycle of p97.

p97 (VCP, Cdc48), a type II AAA+ ATPase family member, is ubiquitous, essential, highly abundant, and involved in a diverse range of biological functions with roles in membrane fusion, endoplasmic-reticulum associated degradation, transcriptional activation, and cell cycle control. As such, dysfunction of this protein has serious pathological consequences and has been implicated in a variety of cancers and neurodegenerative diseases. p97 has a large number of adaptor proteins through which it transmits energy from ATPase activity to conformational changes which are then exerted onto target proteins. p97 has been studied by a variety of biochemical and structural techniques at various resolutions and stages throughout its ATPase cycle. From these studies, many models have been proposed and consequently a single model for p97's action cannot be suggested. Many questions about the mechanism of p97 still remain, including whether the protomers act in a concerted manner and crucially how the induced changes in p97 are transmitted to its adaptor proteins and target substrates. The elucidation of p97's mechanism is not only important in furthering our knowledge of this intriguing protein and its many functions, but subsequently in the development of potential therapies for diseases associated with p97 dysfunction.

Adenosine Triphosphatases↗

PubMed2003

The crystal structure of murine p97/VCP at 3.6A.

p97/VCP is a member of the AAA ATPase family and has roles in both membrane fusion and ubiquitin dependent protein degradation. Here, we present a 3.6A crystal structure of murine p97 in which D2 domain has been modelled as poly-alanine and the remaining approximately 100 residues are absent. The resulting structure illustrates a head-to-tail packing arrangement of the two p97 AAA domains in a natural hexameric state with D1 ADP bound and D2 nucleotide free. The head-to-tail packing arrangement observed in this structure is in contrast to our previously predicted tail-to-tail packing model. The linker between the D1 and D2 domains is partially disordered, suggesting a flexible nature. Normal mode analysis of the crystal structure suggests anti-correlated motions and distinct conformational states of the two AAA domains.

Adenosine Triphosphatases↗