G736S

G736 is wedged between Glu737 (2.41 Angstrom) and Tyr735 (2.47 Angstrom), with a through-space contact cluster reading Arg732 (3.07 Angstrom), His766 (3.29 Angstrom), Ile767 (4.09 Angstrom), Cys733 (4.88 Angstrom), and Leu734 (5.00 Angstrom). The local geometry is structurally complex: a tyrosine-glycine-glutamate sequence sandwiched between an arginine three residues upstream, a histidine six residues downstream by sequence but within 3.3 Angstrom by space, and a free cysteine within 5 Angstrom.

The wild-type glycine at 736 is doing exactly what glycines do best — providing the backbone flexibility that brings Arg732 (3.07 Angstrom), the Tyr735 phenol, and His766 (3.29 Angstrom) into close polar register. The Tyr735 hydroxyl, the Arg732 guanidinium, the Glu737 carboxylate, and the His766 imidazole are all polar-functional groups that the local geometry stages into a hydrogen-bond / electrostatic network. Glycine's job here is to allow the backbone turn that makes this network possible.

Replacing G736 with serine removes the disallowed-region phi/psi freedom and forces the chain into standard geometry. The Tyr735-Arg732-His766 register opens up; the Glu737 contact shifts; the local polar network — which is almost certainly part of the lumenal-domain functional surface — is degraded. DynaMut2's DeltaDeltaG of -1.1 kcal/mol captures the moderate destabilization; AlphaMissense at 0.862 confirms the position is evolutionarily constrained.

The Cys733 at 4.88 Angstrom is a secondary concern. In the wild-type configuration, the geometry holds Cys733 in a defined position relative to the polar cluster. The G736S-induced rearrangement may expose Cys733's thiol to a different local environment, potentially raising disulfide-formation risk in the oxidizing ER lumen. This is inference, not observation, but the structural signature supports it.

ClinVar links G736S to Wolfram syndrome 1, Wolfram-like syndrome, and monogenic hearing loss — phenotypic breadth consistent with partial loss of lumenal-domain function.