In silico prediction of structure and function for a large family of transmembrane proteins that includes human Tmem41b.

Background: Recent strides in computational structural biology have opened up an opportunity to understand previously uncharacterised proteins.  The under-representation of transmembrane proteins in the highlights the need to apply new and advanced bioinformatics methods to shed light on their structure and function.  This study focuses on a family of transmembrane proteins containing the Pfam domain PF09335 ('SNARE_ASSOC'/ 'VTT '/'Tvp38'/'DedA'). One prominent member, Tmem41b, has been shown to be involved in early stages of autophagosome formation and is vital in mouse embryonic development as well as being identified as a viral host factor of SARS-CoV-2. Methods: We used evolutionary covariance-derived information to construct and validate ab initio models, make domain boundary predictions and infer local structural features.  Results: The results from the structural bioinformatics analysis of Tmem41b and its homologues showed that they contain a tandem repeat that is clearly visible in evolutionary covariance data but much less so by sequence analysis.  Furthermore, cross-referencing of other prediction data with covariance analysis showed that the internal repeat features two-fold rotational symmetry.  Ab initio modelling of Tmem41b and homologues reinforces these structural predictions.  Local structural features predicted to be present in Tmem41b were also present in Cl ^-/H ⁺ antiporters.  Conclusions: The results of this study strongly point to Tmem41b and its homologues being transporters for an as-yet uncharacterised substrate and possibly using H ⁺ antiporter activity as its mechanism for transport. Copyright: © 2021 Mesdaghi S et al.

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