Folding cooperativity and allosteric function in the tandem-repeat protein class

Perez-Riba, Albert; Synakewicz, Marie; Itzhaki, Laura S.

doi:10.1098/rstb.2017.0188

Cited by 17 publications

(14 citation statements)

References 74 publications

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“…Thus, some proteins may be characterized by repetition of contiguous homologous domains that are often found in tandem. While tandem repeats are frequently found in the proteome, a clear relationship between the presence of these repetitions and their role in the mechanical and functional properties of proteins remains relatively elusive ( 14 – 16 ).…”

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confidence: 99%

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Gautier

Troilo

Cordier

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Although more than 75% of the proteome is composed of multidomain proteins, current knowledge of protein folding is based primarily on studies of isolated domains. In this work, we describe the folding mechanism of a multidomain tandem construct comprising two distinct covalently bound PDZ domains belonging to a protein called Whirlin, a scaffolding protein of the hearing apparatus. In particular, via a synergy between NMR and kinetic experiments, we demonstrate the presence of a misfolded intermediate that competes with productive folding. In agreement with the view that tandem domain swapping is a potential source of transient misfolding, we demonstrate that such a kinetic trap retains native-like functional activity, as shown by the preserved ability to bind its physiological ligand. Thus, despite the general knowledge that protein misfolding is intimately associated with dysfunction and diseases, we provide a direct example of a functionally competent misfolded state. Remarkably, a bioinformatics analysis of the amino acidic sequence of Whirlin from different species suggests that the tendency to perform tandem domain swapping between PDZ1 and PDZ2 is highly conserved, as demonstrated by their unexpectedly high sequence identity. On the basis of these observations, we discuss on a possible physiological role of such misfolded intermediate.

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confidence: 99%

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Gautier

Troilo

Cordier

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Most of these interactions are observed at the concave surface of the overall HEAT repeat array architecture 125 . The main mechanism behind this versatility is in the overall flexibility inherent to β‐karyopherins leading to multiple levels of allostery, ranging from local to global, and being both competitive and noncompetitive 130,131 . Using these β‐karyopherin data as a template, we speculate that the TPR array of the Pex5 CTD may ultimately have more direct but not yet characterized protein binding partners in addition to well‐established PTS1 cargos, with the ability to regulate cargo binding and ultimately triggering cargo release.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Versatile allosteric properties in Pex5‐like tetratricopeptide repeat proteins to induce diverse downstream function

Bürgi

Ekal

Wilmanns

2021

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Proteins composed of tetratricopeptide repeat (TPR) arrays belong to the α‐solenoid tandem‐repeat family that have unique properties in terms of their overall conformational flexibility and ability to bind to multiple protein ligands. The peroxisomal matrix protein import receptor Pex5 comprises two TPR triplets that recognize protein cargos with a specific C‐terminal Peroxisomal Targeting Signal (PTS) 1 motif. Import of PTS1‐containing protein cargos into peroxisomes through a transient pore is mainly driven by allosteric binding, coupling and release mechanisms, without a need for external energy. A very similar TPR architecture is found in the functionally unrelated TRIP8b, a regulator of the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) ion channel. TRIP8b binds to the HCN ion channel via a C‐terminal sequence motif that is nearly identical to the PTS1 motif of Pex5 receptor cargos. Pex5, Pex5‐related Pex9, and TRIP8b also share a less conserved N‐terminal domain. This domain provides a second protein cargo‐binding site and plays a distinct role in allosteric coupling of initial cargo loading by PTS1 motif‐mediated interactions and different downstream functional readouts. The data reviewed here highlight the overarching role of molecular allostery in driving the diverse functions of TPR array proteins, which could form a model for other α‐solenoid tandem‐repeat proteins involved in translocation processes across membranes.

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“…Often, the folding of proteins with sequential domains is hypothesized to also be sequential, but more complicated folding has also been observed (104 -106). A special class of sequential multidomain proteins are the repeat JBC REVIEWS: Simulating the folding of large proteins proteins, and the folding and misfolding of this class of proteins has recently been reviewed elsewhere (107,108).…”

Section: Simulating the Folding Of Other Large Proteinsmentioning

confidence: 99%

Successes and challenges in simulating the folding of large proteins

Gershenson

Gosavi

Faccioli

et al. 2020

Journal of Biological Chemistry

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Computational simulations of protein folding can be used to interpret experimental folding results, to design new folding experiments, and to test the effects of mutations and small molecules on folding. However, whereas major experimental and computational progress has been made in understanding how small proteins fold, research on larger, multidomain proteins, which comprise the majority of proteins, is less advanced. Specifically, large proteins often fold via long-lived partially folded intermediates, whose structures, potentially toxic oligomerization, and interactions with cellular chaperones remain poorly understood. Molecular dynamics based folding simulations that rely on knowledge of the native structure can provide critical, detailed information on folding free energy landscapes, intermediates, and pathways. Further, increases in computational power and methodological advances have made folding simulations of large proteins practical and valuable. Here, using serpins that inhibit proteases as an example, we review native-centric methods for simulating the folding of large proteins. These synergistic approaches range from Gō and related structurebased models that can predict the effects of the native structure on folding to all-atom-based methods that include side-chain chemistry and can predict how disease-associated mutations may impact folding. The application of these computational approaches to serpins and other large proteins highlights the successes and limitations of current computational methods and underscores how computational results can be used to inform experiments. These powerful simulation approaches in combination with experiments can provide unique insights into how large proteins fold and misfold, expanding our ability to predict and manipulate protein folding.

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Folding cooperativity and allosteric function in the tandem-repeat protein class

Cited by 17 publications

References 74 publications

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Versatile allosteric properties in Pex5‐like tetratricopeptide repeat proteins to induce diverse downstream function

Successes and challenges in simulating the folding of large proteins

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