Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.
Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis.
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Melissa E
ME
Heard
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Roberta
http://orcid.org/0000-0003-1430-2934
R
Besio
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America.
MaryAnn
M
Weis
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America.
Jyoti
J
Rai
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America.
David M
DM
Hudson
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Milena
M
Dimori
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Sarah M
SM
Zimmerman
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Jeffrey A
http://orcid.org/0000-0003-4738-3814
JA
Kamykowski
Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
William R
WR
Hogue
Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Frances L
FL
Swain
Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Marie S
MS
Burdine
Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Samuel G
SG
Mackintosh
Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Alan J
AJ
Tackett
Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Larry J
LJ
Suva
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America.
David R
DR
Eyre
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.|Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Roy
http://orcid.org/0000-0003-1604-4879
R
Morello
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000502:physiology; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis* / Q000378:metabolism; D021983:Cyclophilins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006900:Hydroxylation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000473:pathology; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*
D001324:Autoantigens; C000609794:SC65 protein, mouse; C081786:cyclophilin B; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase; D021983:Cyclophilins