Prolyl hydroxylase domain

The unique Hyp residue may be important both at the molecular and higher-order structure levels in collagen. Bacteria and viruses lack prolyl hydroxylase and have no hydroxyproline in their collagen-like domains. The significant differences in their amino acid composition and sequence compared to animal collagens suggest the use of alternative stabilization strategies for the triple helix (Rasmussen et al., 2003). 

Flashman E, Bagg EAL, Chowdhury R, Mecinovic J, Loenarz C, McDonough MA, Hewitson KS, Schofield CJ. Kinetic rationale for selectivity towards the N- and C-terminal oxygen dependent degradation domain substrates mediated by a loop region of HIF prolyl hydroxylases. J. Biol. Chem. 2008 582 434-438. 

HIF-1 is a heterodimeric transcription factor composed of an alpha subunit (HIF-la) and a constitutively expressed beta subunit (HIF-1 p) [74]. HIF-1 activity is mainly dependent on the level of HIF-la protein [74, 75]. Under hypoxic conditions, HIF-la interacts with HIF-1 p and functions as a transcription factor. Under normoxic conditions, the oxygen-dependent degradation (ODD) domain of HIF-la is hydroxylated by prolyl hydroxylases (PHDs) and ubiquitinated by the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase, resulting in rapid degradation of the HIF-la protein [76, 77]. 

In addition to its role as the P-subunit of PHY, PDI acts independently by catalysing thiol/protein disulphide interchange. The role of PDI as the P-subunit in prolyl 4-hydroxylase is not related to its disulphide isomerase activity and experiments where the vertebrate PDI was mutated in both thioredoxin-like active domains had no effect on tetramer assembly (Vuori et al., 1992). PDI appears to function as a molecular chaperone, retaining the a-subunits in the correct catalytically active, non-aggregated form in the ER-lumen (John et al, 1993). Dissociation of the P-subunits results in insoluble aggregates of the a-subunits, analogous to a-subunits expressed in the absence of PDI. An additional function of PDI in the complex is to maintain the ER luminal location of the a-subunits, since deletion of the ER retention signal from PDI results in the secretion of the complex (Vuori et al., 1992). 

Oxoglutarate-Ee(ll) Oxy superfamily hydroxylation catalytic domain Prolyl 4-hydroxylase alpha subunit N-terminal domain superfamily... 

Prolyl 4-hydroxylase alpha subunit substrate-binding domain (with 2.5 tetratricopeptide motifs) PDI a, a domain (active) W catalytic site -Cys-Gly-His-Cys-PDI b, b domain (inactive) PDI c region (higly acidic)... 

Villar D, Vara-Vega A, Landazuri MO, Del Peso L. Identification of a region on HIF prolyl 4-hydroxylases that determines their specificity for the oxygen degradation domains. Biochem. J. 2007 408 231-240. 

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