Ins and outs of AlphaFold2 transmembrane protein structure predictions

Hegedüs, Tamás; Geisler, Markus; Lukacs, Gergely L.; Farkas, Bianka

doi:10.1007/s00018-021-04112-1

Cited by 103 publications

(100 citation statements)

References 73 publications

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“…It could be used to predict the protein structure at the atomic level with high accuracy. Besides, the protein–protein interactions could be also predicted by AlphaFold2 ( Tunyasuvunakool et al, 2021 ; Hegeds et al, 2022 ). In this study, three SEP proteins, DEFICIENS-like protein (AKC93996.1) and flower meristem identity protein LEAFY (AKC94104.1) in P. henryanum were selected for the prediction of the protein–protein interactions ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

Characterization of Three SEPALLATA-Like MADS-Box Genes Associated With Floral Development in Paphiopedilum henryanum (Orchidaceae)

et al. 2022

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Paphiopedilum (Orchidaceae) is one of the world’s most popular orchids that is found in tropical and subtropical forests and has an enormous ornamental value. SEPALLATA-like (SEP-like) MADS-box genes are responsible for floral organ specification. In this study, three SEP-like MADS-box genes, PhSEP1, PhSEP2, and PhSEP3, were identified in Paphiopedilum henryanum. These genes were 732–916 bp, with conserved SEPI and SEPII motifs. Phylogenetic analysis revealed that PhSEP genes were evolutionarily closer to the core eudicot SEP3 lineage, whereas none of them belonged to core eudicot SEP1/2/4 clades. PhSEP genes displayed non-ubiquitous expression, which was detectable across all floral organs at all developmental stages of the flower buds. Furthermore, subcellular localization experiments revealed the localization of PhSEP proteins in the nucleus. Yeast two-hybrid assays revealed no self-activation of PhSEPs. The protein–protein interactions revealed that PhSEPs possibly interact with B-class DEFICIENS-like and E-class MADS-box proteins. Our study suggests that the three SEP-like genes may play key roles in flower development in P. henryanum, which will improve our understanding of the roles of the SEP-like MADS-box gene family and provide crucial insights into the mechanisms underlying floral development in orchids.

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Section: Resultsmentioning

confidence: 99%

Characterization of Three SEPALLATA-Like MADS-Box Genes Associated With Floral Development in Paphiopedilum henryanum (Orchidaceae)

et al. 2022

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“…The AlphaFold structural database currently has nearly a million protein structures available, including complete proteomes for Homo sapiens and 47 other species ( Jumper et al, 2021 ; Tunyasuvunakool et al, 2021 ). These structures are rapidly facilitating an unprecedented understanding of structural biology ( Hegedus et al, 2022 ; Porta-Pardo et al, 2022 ; Varadi et al, 2022 ; Wehrspan et al, 2022 ). Yet, the accuracy of AlphaFold in terms of predicting otherwise unsolved structures is relatively untested since it only became publicly available less than a year ago.…”

Section: A Case For Differential Regulation By the C-terminal Extensionsmentioning

confidence: 99%

An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms

Hunter

Ferreira

2022

Front. Mol. Biosci.

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5-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in metazoa, fungi, and α-proteobacteria. ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled.

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“…Moreover, in a recent elucidation of a novel membrane protein called ChRmine, some structural features were reported to be mispredicted by AlphaFold 2 ( Kishi et al, 2022 ). However, in a thorough retrospective study ( Hegedűs et al, 2022 ), which used new membrane protein structures reported after the optimization and launch of AlphaFold 2, the program was found to be likely to perform as well with membrane proteins as with water soluble proteins. For both classes of proteins, disordered regions are modeled with low confidence and for the former they are sometimes incorrectly threaded through the membrane.…”

Section: Introductionmentioning

confidence: 99%

AlphaFold 2 and NMR Spectroscopy: Partners to Understand Protein Structure, Dynamics and Function

Laurents

2022

Front. Mol. Biosci.

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The artificial intelligence program AlphaFold 2 is revolutionizing the field of protein structure determination as it accurately predicts the 3D structure of two thirds of the human proteome. Its predictions can be used directly as structural models or indirectly as aids for experimental structure determination using X-ray crystallography, CryoEM or NMR spectroscopy. Nevertheless, AlphaFold 2 can neither afford insight into how proteins fold, nor can it determine protein stability or dynamics. Rare folds or minor alternative conformations are also not predicted by AlphaFold 2 and the program does not forecast the impact of post translational modifications, mutations or ligand binding. The remaining third of human proteome which is poorly predicted largely corresponds to intrinsically disordered regions of proteins. Key to regulation and signaling networks, these disordered regions often form biomolecular condensates or amyloids. Fortunately, the limitations of AlphaFold 2 are largely complemented by NMR spectroscopy. This experimental approach provides information on protein folding and dynamics as well as biomolecular condensates and amyloids and their modulation by experimental conditions, small molecules, post translational modifications, mutations, flanking sequence, interactions with other proteins, RNA and virus. Together, NMR spectroscopy and AlphaFold 2 can collaborate to advance our comprehension of proteins.

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Ins and outs of AlphaFold2 transmembrane protein structure predictions

Cited by 103 publications

References 73 publications

Characterization of Three SEPALLATA-Like MADS-Box Genes Associated With Floral Development in Paphiopedilum henryanum (Orchidaceae)

Characterization of Three SEPALLATA-Like MADS-Box Genes Associated With Floral Development in Paphiopedilum henryanum (Orchidaceae)

An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms

AlphaFold 2 and NMR Spectroscopy: Partners to Understand Protein Structure, Dynamics and Function

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