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bioRxiv · 10.1101/2020.06.27.174763

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

Mesdaghi, S.·Murphy, D. L.·Sanchez Rodriguez, F.·Burgos-Marmol, J. J.·Rigden, D. J.
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Abstract

Recent strides in computational structural biology have opened up an opportunity to understand previously mysterious uncharacterised proteins. The under-representation of transmembrane proteins in the Protein Data Bank highlights the need to apply new and advanced bioinformatics methods to shed light on their structure and function. This study focuses on such a family; transmembrane proteins containing the Pfam domain PF09335 ( SNARE_ASSOC/ VTT / Tvp38). One prominent member, Tmem41b, has been shown to be involved in early stages of autophagosome formation and is vital in mouse embryonic development. Here we use evolutionary covariance-derived information not only to construct and validate ab initio models but also to make domain boundary predictions and infer local structural features. The results from the structural bioinformatics analysis of Tmem41b and its homologues show 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 the covariance analysis shows that the internal repeat features 2-fold rotational symmetry. Ab initio modelling of Tmem41b reinforces these structural predictions. Local structural features predicted to be present in Tmem41b are also present in Cl-/H+ antiporters. These results together strongly point to Tmem41b and its homologues as being transporters for an as-yet uncharacterised substrate and possibly using H+ antiporter activity as its mechanism for transport.

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Mesdaghi, S., Murphy, D. L., Sanchez Rodriguez, F., Burgos-Marmol, J. J., Rigden, D. J.. 2020-06-28. In silico prediction of structure and function for a large family of transmembrane proteins that includes human Tmem41b. https://doi.org/10.1101/2020.06.27.174763

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