Molecular Mechanisms of Collagen Homeostasis
In collaboration with the group of Prof. Paul Gissen at the UCL London, we discovered that VPS33B/VIPAR-mediated trafficking of the human enzyme Procollagen Lysyl 2-Oxoglutarate Dioxygenase 3 (LH3/PLOD3) to newly described cytoplasmic organelles (collagen IV carriers or CIVC) is essential to post-translational modification of de novo generated collagen, its structure and function. This represents the discovery of a novel post-Golgi trafficking pathway that involves previously unrelated sorting proteins and enzymes, also defining roles for the previously uncharacterized VPS33B and VIPAR proteins in regulation of LH3/PLOD3 enzyme functions. VPS33B and VIPAR are deficient in the severe multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome (ARC). Our data provide new insights to understand the molecular mechanisms of this devastating genetic syndrome and related phenotypes.
|Schematic of the newly-discovered pathway targeting LH3 from the trans-Golgi Network to the newly described procollagen containing organelles is regulated by VIPAR and its interacting proteins. Shown on the top-right corner is the homology model of VPS33B-VIPAR interaction, on the right is the crystal structre of full-lenght, dimeric human LH3.|
We have determined the first crystal structure of a full-length human LH enzyme (LH3/PLOD3), providing a structural framework to understand the molecular mechanisms of collagen lysine modification and to rationalize the impact of the numerous disease-related mutations affecting PLOD genes. To further facilitate access to the structural information and mapping of disease-related mutations, we have developed SiMPLOD, a free, manually curated online database which collects all known PLOD mutations and allows their immediate localization on macromolecular structures. SiMPLOD is available at http://fornerislab.unipv.it/SiMPLOD.
Files in Repository:
Full-Length Human Collagen Lysyl Hydroxylases
Encyclopedia of Inorganic and Bioinorganic Chemistry, 2739. (2020) *Equal Contribution
A cooperative network of molecular “hot spots” highlights the complexity of LH3 collagen glycosyltransferase activities
BioRxiv. (2020) *Equal Contribution
Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
Journal of Medical Genetics, 56, 629-638. (2019) - PubMed
SiMPLOD, a structure-integrated database of collagen lysyl hydroxylase (LH/PLOD) enzyme variants.
Journal of Bone and Mineral Research, 34, 1376-1382. (2019) *Equal Contribution - PubMed
Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3.
Nature Communications, 9, 3163. (2018) - PubMed
Autosomal recessive Keratoderma-Ichthyosis-Deafness (ARKID) syndrome is caused by VPS33B mutations affecting Rab protein interaction and collagen modification.
Journal of Investigative Dermatology, S0022-202X, 32800-32807. (2016) - PubMed
Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
Nature Communications, 7, 12111. (2016) *Shared Corresponding Authors - PubMed
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