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. 2022 Jul 12;109(8):1421–1435. doi: 10.1016/j.ajhg.2022.06.008

Figure 2.

Figure 2

Variant locations on protein level and structure of liprin-β1 illustrating the effect of the p.Gly726Val exchange

(A) Location of the variants on protein level aligned to the liprin-β1 isoform 1 (GenBank: NP_003613.4 [GenBank: NM_003622.4]) and count of each variant in the cohort. Truncating and splice-site variants are indicated by red dots, the missense variant is indicated by an orange dot. Abbreviation: SAM, sterile alpha motif.

(B) Structure of SAM2 and SAM3 domains that pair in the wild-type protein. Gly726 is located in a tight turn and makes interactions with Asn803 of the adjacent SAM domain. The contacts are formed between Gly732(Cα) and Asn803(Cβ) (distance = 3.5 Å) and between Gly732(Cα) and Asn803(Cγ) (distance = 3.6 Å). The site of the contacts is marked by a red arrow; Asn803 is shown in grey and Gly726 is colored by atom type. The topology of the protein backbone is schematically depicted with helices in light blue (SAM2 domain) and dark blue (SAM3 domain).

(C) In the Gly726Val variant, a severe steric overlap (yellow circle) between the sidechains of Val726 and Asn803 is observed, which will disrupt the domain interface thereby altering the topology of the SAM domain region.