The critical role of the loops of triosephosphate isomerase for its oligomerization, dynamics, and functionality

Abstract

Triosephosphate isomerase (TIM) catalyzes the reaction to convert dihydroxyacetone phosphate into glyceraldehyde 3-phosphate, and vice versa. In most organisms, its functional oligomeric state is a homodimer; however, tetramer formation in hyperthermophiles is required for functional activity. The tetrameric TIM structure also provides added stability to the structure, enabling it to function at more extreme temperatures. We apply Principal Component Analysis to find that the TIM structure space is clearly divided into two groups-the open and the closed TIM structures. The distribution of the structures in the open set is much sparser than that in the closed set, showing a greater conformational diversity of the open structures. We also apply the Elastic Network Model to four different TIM structures-an engineered monomeric structure, a dimeric structure from a mesophile-Trypanosoma brucei, and two tetrameric structures from hyperthermophiles Thermotoga maritima and Pyrococcus woesei. We find that dimerization not only stabilizes the structures, it also enhances their functional dynamics. Moreover, tetramerization of the hyperthermophilic structures increases their functional loop dynamics, enabling them to function in the destabilizing environment of extreme temperatures. Computations also show that the functional loop motions, especially loops 6 and 7, are highly coordinated. In summary, our computations reveal the underlying mechanism of the allosteric regulation of the functional loops of the TIM structures, and show that tetramerization of the structure as found in the hyperthermophilic organisms is required to maintain the coordination of the functional loops at a level similar to that in the dimeric mesophilic structure.

How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics

“…Previously, N-and C-terminal residues (P169-W171 and K177-A179, respectively) were detected as hinges that drive rigid-lid closure upon binding of the substrate, based on a comparison of one apo and one bound crystal structure (46). Here, however, the loop flexibility in the apo state is apparent in the tip and C-terminal Biophysical Journal 109(6) 1-10 residues, in conformity with previous computational and NMR studies (9,10,45,47,48). In the presence of the inhibitor, the loop's tip residues (especially Ile-173, Gly-174, and Thr-175) become even more flexible.…”

Identification of the critical residues responsible for differential reactivation of the triosephosphate isomerases of two trypanosomes

“…When dimerization takes place the mobility of these loops, together with that of loop 8, is restricted to keep the correct position of the catalytic amino acids. Meanwhile, loops 6 and 7 increase their mobility, so they can continue to protect the catalytic site and allow the entrance of substrates and the liberation of products [28]. …”

Discovery of Functional Motifs from the Interface Region of Oligomeric Proteins Using Frequent Subgraph Mining

“…Eight back loops (BL1-BL8) connect from helix to strand and eight front loops (FL1-FL8 or simply Loop 1−Loop 8) connect from strand to helix. Details can be found in [57] (Fig. 8A).…”