Fold combinations in multi-domain proteins

Naveenkumar, Nagarajan; Kumar, G. Sudesh; Sowdhamini, Ramanathan; Srinivasan, Narayanaswamy; Vishwanath, Sneha

doi:10.6026/97320630015342

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…It might appear challenging to apply our approach to domains found in many distinct domain architectures. However, domain architecture distributions tend to have a long tail, with only a few organizations representing the majority of cases 58 . Here, 16 out of 111 architectures in Pfam that contained CheW‐like domains incorporated ~94% of CheW‐like domains.…”

Section: Discussionmentioning

confidence: 94%

“…However, domain architecture distributions tend to have a long tail, with only a few organizations representing the majority of cases. 58 Here, 16 out of 111 architectures in Pfam that contained CheW-like domains incorporated $94% of CheW-like domains. Of course, individual "rare" architectures of interest could always be manually included with minimal difficulty.…”

Section: Generally Applicable Methods To Analyze Protein Domains As A...mentioning

confidence: 94%

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Generalizable strategy to analyze domains in the context of parent protein architecture: A CheW case study

et al. 2022

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Domains are the three-dimensional building blocks of proteins. An individual domain can occur in a variety of domain architectures that perform unique functions and are subject to different evolutionary selective pressures. We describe an approach to evaluate the variability in amino acid sequences of a single domain across architectural contexts. The ability to distinguish different evolutionary outcomes of one protein domain can help determine whether existing knowledge about a specific domain will apply to an uncharacterized protein, lead to insights and hypotheses about function, and guide experimental priorities. We developed and tested our approach on CheW-like domains (PF01584), which mediate protein/protein interactions and are difficult to compare experimentally. CheW-like domains occur in CheW scaffolding proteins, CheA kinases, and CheV proteins that regulate bacterial chemotaxis. We analyzed 16 domain architectures that included 94% of all CheW-like domains found in nature. We identified six Classes of CheW-like domains with presumed functional differences. CheV and most CheW proteins contained Class 1 domains, whereas some CheW proteins contained Class 6 ($20%) or Class 2 ($1%) domains instead.Most CheA proteins contained Class 3 domains. CheA proteins with multiple Hpt domains contained Class 4 domains. CheA proteins with two CheW-like domains contained one Class 3 and one Class 5. We also created SimpLogo, an innovative method for visualizing amino acid composition across large sets of multiple sequence alignments of arbitrary length. SimpLogo offers substantial advantages over standard sequence logos for comparison and analysis of related protein sequences. The R package for SimpLogo is freely available.

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Section: Discussionmentioning

confidence: 94%

Section: Generally Applicable Methods To Analyze Protein Domains As A...mentioning

confidence: 94%

Generalizable strategy to analyze domains in the context of parent protein architecture: A CheW case study

et al. 2022

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“…Protein domains (most commonly described as structurally and functionally independent protein units) are the basic building blocks by which nature can create an almost unlimited space of combinations. However, nature exploits only a small portion of such portfolio 1 . In addition, only a smaller portion of natural proteins is structurally characterized.…”

Section: Introductionmentioning

confidence: 99%

“…However, nature exploits only a small portion of such portfolio. 1 In addition, only a smaller portion of natural proteins is structurally characterized. The narrow coverage of the three‐dimensional (3D) structure space of proteins is further limited by the fact that almost two‐third of experimentally determined structures are only one‐domain segments of larger existing proteins.…”

Section: Introductionmentioning

confidence: 99%

Fusion of two unrelated protein domains in a chimera protein and its 3D prediction: Justification of the x‐ray reference structures as a prediction benchmark

et al. 2022

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Proteins are naturally formed by domains edging their functional and structural properties. A domain out of the context of an entire protein can retain its structure and to some extent also function on its own. These properties rationalize construction of artificial fusion multidomain proteins with unique combination of various functions. Information on the specific functional and structural characteristics of individual domains in the context of new artificial fusion proteins is inevitably encoded in sequential order of composing domains defining their mutual spatial positions. So the challenges in designing new proteins with new domain combinations lie dominantly in structure/function prediction and its context dependency. Despite the enormous body of publications on artificial fusion proteins, the task of their structure/function prediction is complex and nontrivial. The degree of spatial freedom facilitated by a linker between domains and their mutual orientation driven by noncovalent interactions is beyond a simple and straightforward methodology to predict their structure with reasonable accuracy. In the presented manuscript, we tested methodology using available modeling tools and computational methods. We show that the process and methodology of such prediction are not straightforward and must be done with care even when recently introduced AlphaFold II is used. We also addressed a question of benchmarking standards for prediction of multidomain protein structures—x‐ray or Nuclear Magnetic Resonance experiments. On the study of six two‐domain protein chimeras as well as their composing domains and their x‐ray structures selected from PDB, we conclude that the major obstacle for justified prediction is inappropriate sampling of the conformational space by the explored methods. On the other hands, we can still address particular steps of the methodology and improve the process of chimera proteins prediction.

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“…Due to their implications in cataract, biophysical properties of γ Crys have been studied extensively using both experimental and computational techniques. Studying folding in multidomain proteins is challenging since the domain–domain interactions add to the complexity, as they can influence folding in addition to the intradomain interactions. − Denaturant-induced unfolding experiments ,,, demonstrated a three-state unfolding transition in γ Crys, indicating the presence of a partially structured intermediate state. This intermediate state is structurally characterized for HγD Crys, which consists of a folded Ctd and an unfolded Ntd, , in agreement with the simulations …”

Section: Introductionmentioning

confidence: 99%

Double Domain Swapping in Human γC and γD Crystallin Drives Early Stages of Aggregation

2021

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Human γD (HγD) and γC (HγC) are two-domain crystallin (Crys) proteins expressed in the nucleus of the eye lens. Structural perturbations in the protein often trigger aggregation, which eventually leads to cataract. To decipher the underlying molecular mechanism, it is important to characterize the partially unfolded conformations, which are aggregation-prone. Using a coarse grained protein model and molecular dynamics simulations, we studied the role of on-pathway folding intermediates in the early stages of aggregation. The multidimensional free energy surface revealed at least three different folding pathways with the population of partially structured intermediates. The two dominant pathways confirm sequential folding of the N-terminal [Ntd] and the C-terminal domains [Ctd], while the third, least favored, pathway involves intermediates where both the domains are partially folded. A native-like intermediate (I*), featuring the folded domains and disrupted interdomain contacts, gets populated in all three pathways. I* forms domain swapped dimers by swapping the entire Ntds and Ctds with other monomers. Population of such oligomers can explain the increased resistance to unfolding resulting in hysteresis observed in the folding experiments of HγD Crys. An ensemble of double domain swapped dimers are also formed during refolding, where intermediates consisting of partially folded Ntds and Ctds swap secondary structures with other monomers. The double domain swapping model presented in our study provides structural insights into the early events of aggregation in Crys proteins and identifies the key secondary structural swapping elements, where introducing mutations will aid in regulating the overall aggregation propensity.

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Fold combinations in multi-domain proteins

Cited by 8 publications

References 36 publications

Generalizable strategy to analyze domains in the context of parent protein architecture: A CheW case study

Generalizable strategy to analyze domains in the context of parent protein architecture: A CheW case study

Fusion of two unrelated protein domains in a chimera protein and its 3D prediction: Justification of the x‐ray reference structures as a prediction benchmark

Double Domain Swapping in Human γC and γD Crystallin Drives Early Stages of Aggregation

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