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- Govindarajan, Sudha, et al.
(författare)
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The evolutionary history of topological variations in the CPA/AT superfamily
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- CPA/AT transporters consist of two structurally and evolutionarily related inverted repeat units, each of them with one core and one scaffold subdomain. During evolution, these families have undergone substantial changes in structure, topology and function. Central to the function of the transporters is the existence of two noncanonical helices that are involved in the transport process. In different families, two different types of these helices have been identified, reentrant and broken. Here, we use an integrated topology annotation method to identify novel topologies in the families. It combines topology prediction, similarity to families with known structure, and the difference in positively charged residues present in inside and outside loops in alternative topological models. We identified families with diverse topologies containing broken or reentrant helix. We classified all families based on 3 distinct evolutionary groups that each share a structurally similar C-terminal repeat unit newly termed as “Fold-types”. Using the evolutionary relationship between families we propose topological transitions including, a transition between broken and reentrant helices, complete change of orientation, changes in the number of scaffold helices and even in some rare cases, losses of core helices. The evolutionary history of the repeat units shows gene duplication and repeat shuffling events to result in these extensive topology variations. The novel structure-based classification, together with supporting structural models and other information, is presented in a searchable database, CPAfold (cpafold.bioinfo.se). Our comprehensive study of topology variations within the CPA superfamily provides better insight about their structure and evolution.
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| 2. |
- Sudha, Govindarajan, et al.
(författare)
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The evolutionary history of topological variations in the CPA/AT transporters
- 2021
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- CPA/AT transporters are made up of scaffold and a core domain. The core domain contains two non-canonical helices (broken or reentrant) that mediate the transport of ions, amino acids or other charged compounds. During evolution, these transporters have undergone substantial changes in structure, topology and function. To shed light on these structural transitions, we create models for all families using an integrated topology annotation method. We find that the CPA/AT transporters can be classified into four fold-types based on their structure; (1) the CPA-broken fold-type, (2) the CPA-reentrant fold-type, (3) the BART fold-type, and (4) a previously not described fold-type, the Reentrant-Helix-Reentrant fold-type. Several topological transitions are identified, including the transition between a broken and reentrant helix, one transition between a loop and a reentrant helix, complete changes of orientation, and changes in the number of scaffold helices. These transitions are mainly caused by gene duplication and shuffling events. Structural models, topology information and other details are presented in a searchable database, CPAfold (cpafold.bioinfo.se). Author summary The availability of experimentally solved transmembrane transport structures are sparse, and modelling is challenging as the families contain non-canonical transmembrane helices. Here, we present structural models for all families of CPA/AT transporters. These proteins are then classified into four fold-types, including one novel fold-type, the reentrant-helix-reentrant fold type. We find extensive structural variations within the fold with members having from three to fourteen transmembrane helices. We explore the evolutionary mechanisms that have shaped the topological variations providing a deeper understanding of membrane protein structure and evolution. We also believe our work could serve as a model system to understand the evolution of topology variations for other membrane proteins.
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