Natasha Trajkovska - Academia.edu (original) (raw)

Uploads

Papers by Natasha Trajkovska

Research paper thumbnail of The Hidden Intricacies of Aquaporins: Remarkable Details in a Common Structural Scaffold

Small

Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow thr... more Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow through cell membranes at no expense of solute discrimination. In spite of a plethora of solved AQP structures, many structural details remain hidden. Here, by combining extensive sequence-and structural-based analysis of a unique set of 20 non-redundant high-resolution structures and molecular dynamics simulations of 4 representatives, we identify key aspects of AQP stability, gating, selectivity, pore geometry and oligomerization, with a potential impact on channel functionality. We challenge the general view of AQPs possessing a continuous open water pore and depict that AQPs selectivity is not exclusively shaped by pore lining residues but also by the relative arrangement of transmembrane helices. Moreover, our analysis reveals that hydrophobic interactions constitute the main determinant of protein thermal stability. Finally, we establish a novel numbering scheme of the conserved AQP scaffold facilitating direct comparison and prediction of potential structural effects of e.g. disease-causing mutations. Additionally, our results pave the way for the design of optimized AQP water channels to be utilized in biotechnological applications. 1. Introduction Aquaporins (AQPs), part of a larger family of major intrinsic proteins, are one of the best studied protein families with currently 20 non-redundant high-resolution structures (≤3,70 Å) solved. Since their first discovery in 1992 by Peter Agre and coworkers (1, 2), thirteen different types of aquaporins (AQP0-12) were discovered in mammals (3). The narrow AQP pores combine enormous permeability, conducting water in a single-file manner close to the diffusion limit of water in bulk, with exceptional selectivity (4). A subset of AQPs, the aquaglyceroporins (AQGPs), paralogs of AQPs, are also able to conduct glycerol and other small neutral solutes (5, 6). Bacteria also express members of AQPs and AQGPs, generally functioning with one copy of each paralog and, interestingly, some lacking both. Unicellular eukaryotes and fungi follow a similar pattern, with a clear division between AQPs or AQGPs and a heterogeneous distribution in the number of copies of each paralog in the different genera (7). So far, no archaea has been found that possesses both paralogs concurrently. Plants exhibit the highest AQP diversity, with five main subfamilies (plasma membrane intrinsic proteins (PIPs), tonoplast intrinsic proteins (TIPs), nodulin-26 like intrinsic proteins (NIPs), small basic intrinsic proteins (SIPs) and X intrinsic proteins (XIPs)), which are each further divided into subgroups (7). Furthermore, in primitive plant species, two additional subfamilies, GLPF-like intrinsic proteins (GIPs) and hybrid intrinsic proteins (HIPs), have been found (8). However, the full diversity of AQ(G)Ps is still not represented by the numerous high-resolution structures, as exemplified by only three plant aquaporin structures and none of the unorthodox AQ(G)Ps (represented by AQP11 and 12 in mammals).

Research paper thumbnail of The Hidden Intricacies of Aquaporins: Remarkable Details in a Common Structural Scaffold

Small

Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow thr... more Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow through cell membranes at no expense of solute discrimination. In spite of a plethora of solved AQP structures, many structural details remain hidden. Here, by combining extensive sequence-and structural-based analysis of a unique set of 20 non-redundant high-resolution structures and molecular dynamics simulations of 4 representatives, we identify key aspects of AQP stability, gating, selectivity, pore geometry and oligomerization, with a potential impact on channel functionality. We challenge the general view of AQPs possessing a continuous open water pore and depict that AQPs selectivity is not exclusively shaped by pore lining residues but also by the relative arrangement of transmembrane helices. Moreover, our analysis reveals that hydrophobic interactions constitute the main determinant of protein thermal stability. Finally, we establish a novel numbering scheme of the conserved AQP scaffold facilitating direct comparison and prediction of potential structural effects of e.g. disease-causing mutations. Additionally, our results pave the way for the design of optimized AQP water channels to be utilized in biotechnological applications. 1. Introduction Aquaporins (AQPs), part of a larger family of major intrinsic proteins, are one of the best studied protein families with currently 20 non-redundant high-resolution structures (≤3,70 Å) solved. Since their first discovery in 1992 by Peter Agre and coworkers (1, 2), thirteen different types of aquaporins (AQP0-12) were discovered in mammals (3). The narrow AQP pores combine enormous permeability, conducting water in a single-file manner close to the diffusion limit of water in bulk, with exceptional selectivity (4). A subset of AQPs, the aquaglyceroporins (AQGPs), paralogs of AQPs, are also able to conduct glycerol and other small neutral solutes (5, 6). Bacteria also express members of AQPs and AQGPs, generally functioning with one copy of each paralog and, interestingly, some lacking both. Unicellular eukaryotes and fungi follow a similar pattern, with a clear division between AQPs or AQGPs and a heterogeneous distribution in the number of copies of each paralog in the different genera (7). So far, no archaea has been found that possesses both paralogs concurrently. Plants exhibit the highest AQP diversity, with five main subfamilies (plasma membrane intrinsic proteins (PIPs), tonoplast intrinsic proteins (TIPs), nodulin-26 like intrinsic proteins (NIPs), small basic intrinsic proteins (SIPs) and X intrinsic proteins (XIPs)), which are each further divided into subgroups (7). Furthermore, in primitive plant species, two additional subfamilies, GLPF-like intrinsic proteins (GIPs) and hybrid intrinsic proteins (HIPs), have been found (8). However, the full diversity of AQ(G)Ps is still not represented by the numerous high-resolution structures, as exemplified by only three plant aquaporin structures and none of the unorthodox AQ(G)Ps (represented by AQP11 and 12 in mammals).