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Structure and stability of the designer protein WRAP-T and its permutants.

ABSTRACT: [Formula: see text]-Propeller proteins are common natural disc-like pseudo-symmetric proteins that contain multiple repeats ('blades') each consisting of a 4-stranded anti-parallel [Formula: see text]-sheet. So far, 4- to 12-bladed [Formula: see text]-propellers have been discovered in nature showing large functional and sequential variation. Using computational design approaches, we created perfectly symmetric [Formula: see text]-propellers out of natural pseudo-symmetric templates. These proteins are useful tools to study protein evolution of this very diverse fold. While the 7-bladed architecture is the most common, no symmetric 7-bladed monomer has been created and characterized so far. Here we describe such a engineered protein, based on a highly symmetric natural template, and test the effects of circular permutation on its stability. Geometrical analysis of this protein and other artificial symmetrical proteins reveals no systematic constraint that could be used to help in engineering of this fold, and suggests sequence constraints unique to each [Formula: see text]-propeller sub-family.

SUBMITTER: Mylemans B

PROVIDER: S-EPMC8458387 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Structure and stability of the designer protein WRAP-T and its permutants.

Mylemans Bram B Lee Xiao Yin XY Laier Ina I Helsen Christine C Voet Arnout R D ARD

Scientific reports 20210922 1

[Formula: see text]-Propeller proteins are common natural disc-like pseudo-symmetric proteins that contain multiple repeats ('blades') each consisting of a 4-stranded anti-parallel [Formula: see text]-sheet. So far, 4- to 12-bladed [Formula: see text]-propellers have been discovered in nature showing large functional and sequential variation. Using computational design approaches, we created perfectly symmetric [Formula: see text]-propellers out of natural pseudo-symmetric templates. These prote ...[more]

PMID: 34552189

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Project description:Predicting changes in protein thermostability due to amino acid substitutions is essential for understanding human diseases and engineering useful proteins for clinical and industrial applications. While recent advances in protein generative models, which learn probability distributions over amino acids conditioned on structural or evolutionary sequence contexts, have shown impressive performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability does not extend to all protein functions. In particular, their potential to improve protein stability prediction remains underexplored. In this work, we present SPURS, a novel deep learning framework that adapts and integrates two general-purpose protein generative models-a protein language model (ESM) and an inverse folding model (ProteinMPNN)-into an effective stability predictor. SPURS employs a lightweight neural network module to rewire per-residue structure representations learned by ProteinMPNN into the attention layers of ESM, thereby informing and enhancing ESM's sequence representation learning. This rewiring strategy enables SPURS to harness evolutionary patterns from both sequence and structure data, where the sequence likelihood distribution learned by ESM is conditioned on structure priors encoded by ProteinMPNN to predict mutation effects. We steer this integrated framework to a stability prediction model through supervised training on a recently released mega-scale thermostability dataset. Evaluations across 12 benchmark datasets showed that SPURS delivers accurate, rapid, scalable, and generalizable stability predictions, consistently outperforming current state-of-the-art methods. Notably, SPURS demonstrates remarkable versatility in protein stability and function analyses: when combined with a protein language model, it accurately identifies protein functional sites in an unsupervised manner. Additionally, it enhances current low-N protein fitness prediction models by serving as a stability prior model to improve accuracy. These results highlight SPURS as a powerful tool to advance current protein stability prediction and machine learning-guided protein engineering workflows. The source code of SPURS is available at https://github.com/luo-group/SPURS.

Dataset Information

Structure and stability of the designer protein WRAP-T and its permutants.

Publications

Structure and stability of the designer protein WRAP-T and its permutants.

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