hGGCX structural model characteristics
In order to understand the specific structural implication of the
reported pathogenic variants a threading based GGCX in silicomodel was generated. In the simulation-equilibrated model, the majority
of the C-terminal region from 420-758aa localized towards the ER luminal
side including the propeptide binding site (495-513aa) (Parker et al.,
2014) (Figure S3). Our model has
multiple transmembrane domains with a distribution of both proper
helices (116-134, 240-262, 274-292, 362-377aa) and molten globule
regions (95-115, 394-419aa) resembling loosely packed helical structure,
which also bears the glutamate binding site (393-404aa) (Figure S3)
(Mutucumarana et al., 2000; Mutucumarana, Acher, Straight, Jin, &
Stafford, 2003). In the absence of adequate structural templates and
considering the large size of GGCX, our in silico model, albeit
entirely hypothetical reflects the best possible structural
representation of GGCX protein that can be achieved presently. ReportedGGCX variants are heterogeneously distributed throughout thisin silico model (Figure S4).