A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis [Enzymology]

May 12th, 2014 by Ishikawa, Y., Bachinger, H. P.

The biosynthesis of collagens occurs in the rough endoplasmic reticulum (rER) and requires a large numbers of molecular chaperones, foldases and post-translational modification enzymes. Collagens contain a large number of proline residues that are post-translationally modified to 3-hydroxyproline or 4-hydroxyproline and the rate-limiting step in formation of the triple helix is the cis-trans isomerization of peptidyl-proline bonds. This step is catalyzed by peptidyl-prolyl cis-trans isomerases (PPIases). There are seven PPIases in the rER and so far two of these enzymes, cyclophilin B (CypB) and FKBP65 were shown to be involved in collagen biosynthesis. The absence of either CypB or FKBP65 leads to a recessive form of Osteogenesis Imperfecta (OI). The absence of FKBP22 leads to a kyphoscoliotic type of Ehlers-Danlos Syndrome (EDS) and this type of EDS is classified as EDS type VI, which can also be caused by a deficiency in lysyl-hydroxylase 1 (LH1). However, the lack of FKBP22 shows a wider spectrum of clinical phenotypes than the absence of LH1 and additionally includes myopathy, hearing loss and aortic rupture. Here we show that FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen and type X collagen, but not with type I collagen, type II collagen or type V collagen. These restrictive interactions might help explain the broader phenotype observed in patients that lack FKBP22.