Details

Autor(en) / Beteiligte

• Gorelik, Alexei
• Illes, Katalin
• Bui, Khanh Huy
• Nagar, Bhushan

Titel

Structures of the mannose-6-phosphate pathway enzyme, GlcNAc-1-phosphotransferase

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2022-08, Vol.119 (33), p.e2203518119-e2203518119

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The mannose-6-phosphate (M6P) pathway is responsible for the transport of hydrolytic enzymes to lysosomes. N-acetylglucosamine-1-phosphotransferase (GNPT) catalyzes the first step of tagging these hydrolases with M6P, which when recognized by receptors in the Golgi diverts them to lysosomes. Genetic defects in the GNPT subunits, GNPTAB and GNPTG, cause the lysosomal storage diseases mucolipidosis types II and III. To better understand its function, we determined partial three-dimensional structures of the GNPT complex. The catalytic domain contains a deep cavity for binding of uridine diphosphate- -acetylglucosamine, and the surrounding residues point to a one-step transfer mechanism. An isolated structure of the gamma subunit of GNPT reveals that it can bind to mannose-containing glycans in different configurations, suggesting that it may play a role in directing glycans into the active site. These findings may facilitate the development of therapies for lysosomal storage diseases.