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Research Themes Infectious diseases

Protein Folding and Misfolding: It's the Journey, Not the Destination

SBKB [doi:10.1038/sbkb.2015.4]
Technical Highlight - March 2015
Short description: Computational analysis suggests ∼10% of pathogenic mutations interfere with membrane integration.

10% of pathogenic mutations in transmembrane helices are predicted to disrupt membrane integration or orientation. Figure adapted from Schlebach and Sanders 1 with kind permission from Springer Science and Business Media.


Protein maturation requires several steps to reach correct localization and active conformation. For membrane proteins, one of these steps is the cotranslational insertion of transmembrane helices into the endoplasmic reticulum membrane, as mediated by the translocon. This process is sensitive to environmental conditions and other factors, meaning that even native sequences can sometimes fail to insert properly. The extent to which pathogenic mutations in membrane proteins might exacerbate the challenges of membrane insertion is not well understood.

To gain insight into this question, Schlebach and Sanders (PSI MPSbyNMR) identified five transmembrane proteins for which clinical data on pathogenic mutations are available, including rhodopsin. The authors then used the ΔG prediction algorithm, published in 2007 by the von Heijne group, to determine the energetics of inserting each of the 36 individual transmembrane helices from these proteins into the membrane and to confirm the location of transmembrane sequences within each full protein.

With a baseline set for the wild-type sequences, the authors parsed the known pathogenic mutations in these proteins to identify 470 amino acid changes in or near the transmembrane helices. Analysis of this collection with the prediction algorithm identified both membrane insertion-stabilizing and destabilizing mutations. The location scan also identified several mutations that were predicted to cause a shift in the placement of the helix, with the largest shift calculated at 11 residues.

Finally, the authors compared published data on the cellular behavior of 22 rhodopsin mutants with their predictions to determine if the computationally destabilizing mutations correlated with delays in trafficking or increased degradation. Indeed, 15 of the mutants, as predicted, had minimal impact on the folding pathway, whereas 6 other mutations predicted to destabilize membrane integration caused retention of the protein in the endoplasmic reticulum and less activity overall. However, the L125R mutant, predicted to destabilize helix insertion, seemed to traffic normally; upon re-inspection of the sequence, the authors suspect an intra- or interhelical salt bridge could explain this result.

While the authors note that these predictions should be examined biochemically, their results highlight the importance of membrane insertion in disease etiology and point to new opportunities to resolve mutant phenotypes via early intervention.

Catherine Goodman

References

  1. J.P. Schlebach & C.R. Sanders Influence of pathogenic mutations on the energetics of translocon-mediated bilayer integration of transmembrane helices.
    J. Membrane Biol. (6 September 2014). doi:10.1007/s00232-014-9726-0

  2. T. Hessa et al. Molecular code for transmembrane-helix recognition by the Sec61 translocon.
    Nature. 450, 1026-1030 (2007). doi:10.1038/nature06387

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