RT Journal Article
SR Electronic
T1 Structure and mechanism of LARGE1 matriglycan polymerase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.12.491222
DO 10.1101/2022.05.12.491222
A1 Soumya Joseph
A1 Nicholas J. Schnicker
A1 Zhen Xu
A1 Tiandi Yang
A1 Jesse Hopkins
A1 Maxwell Watkins
A1 Srinivas Chakravarthy
A1 Omar Davulcu
A1 Mary E. Anderson
A1 David Venzke
A1 Kevin P. Campbell
YR 2022
UL http://biorxiv.org/content/early/2022/05/12/2022.05.12.491222.abstract
AB Matriglycan is a linear polysaccharide of alternating xylose and glucuronate that binds extracellular matrix proteins and acts as a receptor for Lassa fever virus. LARGE1 synthesizes matriglycan on dystroglycan and mutations in LARGE1 cause muscular dystrophy with abnormal brain development. However, the mechanism of matriglycan polymerization by LARGE1 is unknown. Here, we report the cryo-EM structure of LARGE1. We show that LARGE1 functions as a dimer to polymerize matriglycan by alternating activities between the xylose transferase domain on one protomer and the glucuronate transferase domain on the other protomer. Biochemical analyses using a recombinant Golgi form of dystroglycan reveal that LARGE1 polymerizes matriglycan processively. Our results provide mechanistic insights into LARGE1 function and may facilitate novel therapeutic strategies for treating neuromuscular disorders or arenaviral infections.One-Sentence Summary Dimeric LARGE1 processively polymerizes matriglycan on dystroglycan using orthogonal active sites on alternate protomers.Competing Interest StatementThe authors have declared no competing interest.