7s06

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Polymerization of actin into cytoskeletal filaments is coupled to its bound adenine nucleotides. The mechanism by which nucleotide modulates actin functions has not been evident from analyses of ATP- and ADP-bound crystal structures of the actin monomer. We report that NMR chemical shift differences between the two forms are globally distributed. Furthermore, microsecond-millisecond motions are spread throughout the molecule in the ATP form, but largely confined to subdomains 1 and 2, and the nucleotide binding site in the ADP form. Through these motions, the ATP- and ADP-bound forms sample different high-energy conformations. A deafness-causing, fast-nucleating actin mutant populates the high-energy conformer of ATP-actin more than the wild-type protein, suggesting that this conformer may be on the pathway to nucleation. Together, the data suggest a model in which differential sampling of a nucleation-compatible form of the actin monomer may contribute to control of actin filament dynamics by nucleotide.
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Vertebrates use the mannose 6-phosphate (M6P)-recognition system to deliver lysosomal hydrolases to lysosomes. Key to this pathway is N-acetylglucosamine (GlcNAc)-1-phosphotransferase (PTase) that selectively adds GlcNAc-phosphate (P) to mannose residues of hydrolases. Human PTase is an alpha2beta2gamma2 heterohexamer with a catalytic core and several peripheral domains that recognize and bind substrates. Here we report a cryo-EM structure of the catalytic core of human PTase and the identification of a hockey stick-like motif that controls activation of the enzyme. Movement of this motif out of the catalytic pocket is associated with a rearrangement of part of the peripheral domains that unblocks hydrolase glycan access to the catalytic site, thereby activating PTase. We propose that PTase fluctuates between inactive and active states in solution, and selective substrate binding of a lysosomal hydrolase through its protein-binding determinant to PTase locks the enzyme in the active state to permit glycan phosphorylation. This mechanism would help ensure that only N-linked glycans of lysosomal enzymes are phosphorylated.
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Bound nucleotide can control the dynamic architecture of monomeric actin.,Ali R, Zahm JA, Rosen MK Nat Struct Mol Biol. 2022 Mar 24. pii: 10.1038/s41594-022-00743-5. doi:, 10.1038/s41594-022-00743-5. PMID:35332323<ref>PMID:35332323</ref>
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Structure of the human GlcNAc-1-phosphotransferase alphabeta subunits reveals regulatory mechanism for lysosomal enzyme glycan phosphorylation.,Li H, Lee WS, Feng X, Bai L, Jennings BC, Liu L, Doray B, Canfield WM, Kornfeld S, Li H Nat Struct Mol Biol. 2022 Mar 24. pii: 10.1038/s41594-022-00748-0. doi:, 10.1038/s41594-022-00748-0. PMID:35332324<ref>PMID:35332324</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 10:22, 13 April 2022

Cryo-EM structure of human GlcNAc-1-phosphotransferase A2B2 subcomplex

PDB ID 7s06

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