Accurate contact-based modelling of repeat proteins predicts the structure of new repeats protein families

Bassot, Claudio; Elofsson, Arne

doi:10.1371/journal.pcbi.1008798

Cited by 9 publications

(5 citation statements)

References 46 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We modeled the Spike-hACE2 binding using trRosetta, the current state-of-the-art in rapid and reliable de novo prediction of protein structure. This tool has been used to add more than 6000 protein structures from 41 protein families listed in the pfam database, and it has shown an accuracy over 90% in fidelity with ground truth experimental structures [56,57]. Our results suggest that the protein generated by the proposed recombination event involving ancestral strains of SARS-CoV/ SARS-CoV-2 increased affinity to hACE2.…”

Section: Discussionmentioning

confidence: 82%

Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

Background The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses the receptor binding domain (RBD) of the Spike protein, which is responsible for viral binding to host cell receptors. In this work, we reconstruct the evolutionary events that have accompanied the emergence of SARS-CoV-2, with a special emphasis on the RBD and its adaptation for binding to its receptor, human ACE2. Methods By means of phylogenetic and recombination analyses, we found evidence of a recombination event in the RBD involving ancestral linages to both SARS-CoV and SARS-CoV-2. We then assessed the effect of this recombination at protein level by reconstructing the RBD of the closest ancestors to SARS-CoV-2, SARS-CoV, and other Sarbecoviruses, including the most recent common ancestor of the recombining clade. The resulting information was used to measure and compare, in silico, their ACE2-binding affinities using the physics-based trRosetta algorithm. Results We show that, through an ancestral recombination event, SARS-CoV and SARS-CoV-2 share an RBD sequence that includes two insertions (positions 432-436 and 460-472), as well as the variants 427N and 436Y. Both 427N and 436Y belong to a helix that interacts directly with the human ACE2 (hACE2) receptor. Reconstruction of ancestral states, combined with protein-binding affinity analyses, suggests that the recombination event involving ancestral strains of SARS-CoV and SARS-CoV-2 led to an increased affinity for hACE2 binding and that alleles 427N and 436Y significantly enhanced affinity as well. Conclusions We report an ancestral recombination event affecting the RBD of both SARS-CoV and SARS-CoV-2 that was associated with an increased binding affinity to hACE2. Structural modeling indicates that ancestors of SARS-CoV-2 may have acquired the ability to infect humans decades ago. The binding affinity with the human receptor would have been subsequently boosted in SARS-CoV and SARS-CoV-2 through further mutations in RBD.

show abstract

Section: Discussionmentioning

confidence: 82%

Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

show abstract

“…To extract only true contacts from correlated mutations, state-of-the-art contact map predictors employ deep networks ( 21 ). Herein, we used four contact maps predictors, which were identified as accurate ( 21 – 24 ): RaptorX ( 18 ), TripletRes ( 25 ), trRosetta ( 26 ), and DeepMetaPSICOV ( 27 ).…”

Section: Resultsmentioning

confidence: 99%

“…Accurate prediction of contact maps requires multiple sequence alignments of many diverse and homologous sequences ( 4 , 18 , 24 ); when only a few homologs are available, predictions tend to be of low quality. For example, 148 effective homologs were needed by RaptorX to reach an accuracy of 0.55 (in a 0-through-1 scale) in the top L/5 medium-range contacts in membrane proteins (L being sequence length) ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

Gram-negative outer-membrane proteins with multiple β-barrel domains

Solan

Pereira

Lupas

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Outer-membrane beta barrels (OMBBs) are found in the outer membrane of gram-negative bacteria and eukaryotic organelles. OMBBs fold as antiparallel β-sheets that close onto themselves, forming pores that traverse the membrane. Currently known structures include only one barrel, of 8 to 36 strands, per chain. The lack of multi-OMBB chains is surprising, as most OMBBs form oligomers, and some function only in this state. Using a combination of sensitive sequence comparison methods and coevolutionary analysis tools, we identify many proteins combining multiple beta barrels within a single chain; combinations that include eight-stranded barrels prevail. These multibarrels seem to be the result of independent, lineage-specific fusion and amplification events. The absence of multibarrels that are universally conserved in bacteria with an outer membrane, coupled with their frequent de novo genesis, suggests that their functions are not essential but rather beneficial in specific environments. Adjacent barrels of complementary function within the same chain may allow for functions beyond those of the individual barrels.

show abstract

“…This study employs deep learning modelling methods to argue for a revised topology for Oca2. Deep learning methods such as DMPfold (Greener, Kandathil, & Jones, 2019), trRosetta (Bassot & Elofsson, 2021) and AlphaFold2 (Jumper et al, 2021) build predicted protein structures by predicting inter residue distances, main chain hydrogen bond network and torsion angles and utilizing these as restraints in the model building process. Benchmarking these methods have demonstrated that they work just as well for membrane proteins as they do for soluble proteins (Greener et al, 2019; Hegedűs, Geisler, Lukács, & Farkas, 2022).…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Pink-eyed Dilution Protein (Oca2)

Mesdaghi

Murphy

Simpkin

et al. 2022

Preprint

View full text Add to dashboard Cite

Recent innovations in computational structural biology have opened an opportunity to revise our current understanding of the structure and function of clinically important proteins. This study centres on human Oca2 which is located on mature melanosomal membranes. Mutations of Oca2 can result in a form of oculocutanous albinism which is the most prevalent and visually identifiable form of albinism. Sequence analysis predicts Oca2 to be a member of the SLC13 transporter family but it has not been classified into any existing SLC families. The modelling of Oca2 with AlphaFold2 and other advanced methods shows that, like SLC13 members, it consists of a scaffold and transport domain and displays a pseudo inverted repeat topology that includes re-entrant loops. This finding contradicts the prevailing consensus view of its topology. In addition to the scaffold and transport domains the presence of a cryptic GOLD domain is revealed that is likely responsible for its trafficking from the endoplasmic reticulum to the Golgi prior to localisation at the melanosomes and possesses known glycosylation sites. Analysis of the putative ligand binding site of the model shows the presence of highly conserved key asparagine residues that suggest Oca2 may be a Na+/dicarboxylate symporter. Known critical pathogenic mutations map to structural features present in the repeat regions that form the transport domain. Exploiting the AlphaFold2 multimeric modelling protocol in combination with conventional homology modelling allowed the building of a plausible homodimer in both an inward- and outward-facing conformation supporting an elevator-type transport mechanism.

show abstract

Accurate contact-based modelling of repeat proteins predicts the structure of new repeats protein families

Cited by 9 publications

References 46 publications

Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

Gram-negative outer-membrane proteins with multiple β-barrel domains

Structural Insights into Pink-eyed Dilution Protein (Oca2)

Contact Info

Product

Resources

About