Structure and transport mechanism of P5B-ATPases
(2021) In Nature Communications 12(1).- Abstract
In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined... (More)
In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined by transmembrane segments 2, 4 and 6. Despite the dramatically different nature of the transported cargo, these findings pinpoint shared principles of transport and regulation among the evolutionary related P4-, P5A- and P5B-ATPases. The data also provide a framework for analysis of associated maladies, such as Parkinson’s disease.
(Less)
- author
- Li, Ping LU ; Wang, Kaituo ; Salustros, Nina ; Grønberg, Christina and Gourdon, Pontus LU
- organization
- publishing date
- 2021-12-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 12
- issue
- 1
- article number
- 3973
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:34172751
- scopus:85109197402
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-021-24148-y
- language
- English
- LU publication?
- yes
- id
- 1ac36294-a4e2-4b20-a51c-6b497a7c6011
- date added to LUP
- 2021-08-12 10:44:50
- date last changed
- 2024-04-06 06:36:49
@article{1ac36294-a4e2-4b20-a51c-6b497a7c6011, abstract = {{<p>In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined by transmembrane segments 2, 4 and 6. Despite the dramatically different nature of the transported cargo, these findings pinpoint shared principles of transport and regulation among the evolutionary related P4-, P5A- and P5B-ATPases. The data also provide a framework for analysis of associated maladies, such as Parkinson’s disease.</p>}}, author = {{Li, Ping and Wang, Kaituo and Salustros, Nina and Grønberg, Christina and Gourdon, Pontus}}, issn = {{2041-1723}}, language = {{eng}}, month = {{12}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Structure and transport mechanism of P5B-ATPases}}, url = {{http://dx.doi.org/10.1038/s41467-021-24148-y}}, doi = {{10.1038/s41467-021-24148-y}}, volume = {{12}}, year = {{2021}}, }