Editorial Overview: Single-Molecule Approaches to Difficult Challenges in Folding and Dynamics

Zhang, Yongli; Ha, Taekjip; Marqusee, Susan

doi:10.1016/j.jmb.2017.12.019

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…The type Ⅱ Western CagA utilizes the tandem repeats of the EPIpYA-C as bis-P segment to elevate its stimulatory capability for SHP2. In contrast, the East Asian CagA with mono-P EPIpYA-D rarely duplicates ( 49 , 50 ).…”

Section: Discussionmentioning

confidence: 94%

A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism

Tao

Xie

Zhong

et al. 2021

Journal of Biological Chemistry

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The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a “multiple gear” regulatory mechanism, in which different activators ( e.g., insulin receptor substrate-1 and CagA), oncogenic mutations ( e.g., E76A), and allosteric inhibitors ( e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.

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Section: Discussionmentioning

confidence: 94%

A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism

Tao

Xie

Zhong

et al. 2021

Journal of Biological Chemistry

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“…SM techniques (SMTs) have unique advantages of recording the behavior of individual molecules in a heterogeneous sample (Seisenberger et al ., 2001; Zhang et al ., 2018). The required concentration for most SMTs is close to the endogenous level (pM to nM).…”

Section: Introductionmentioning

confidence: 99%

Single-molecule studies of amyloid proteins: from biophysical properties to diagnostic perspectives

Cao

Loch

et al. 2020

Quart. Rev. Biophys.

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In neurodegenerative diseases, a wide range of amyloid proteins or peptides such as amyloid-beta and α-synuclein fail to keep native functional conformations, followed by misfolding and self-assembling into a diverse array of aggregates. The aggregates further exert toxicity leading to the dysfunction, degeneration and loss of cells in the affected organs. Due to the disordered structure of the amyloid proteins, endogenous molecules, such as lipids, are prone to interact with amyloid proteins at a low concentration and influence amyloid cytotoxicity. The heterogeneity of amyloid proteinscomplicates the understanding of the amyloid cytotoxicity when relying only on conventional bulk and ensemble techniques. As complementary tools, single-molecule techniques (SMTs) provide novel insights into the different subpopulations of a heterogeneous amyloid mixture as well as the cytotoxicity, in particular as involved in lipid membranes. This review focuses on the recent advances of a series of SMTs, including single-molecule fluorescence imaging, single-molecule force spectroscopy and single-nanopore electrical recording, for the understanding of the amyloid molecular mechanism. The working principles, benefits and limitations of each technique are discussed and compared in amyloid protein related studies.. We also discuss why SMTs show great potential and are worthy of further investigation with feasibility studies as diagnostic tools of neurodegenerative diseases and which limitations are to be addressed.

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Energetics, kinetics, and pathways of SNARE assembly in membrane fusion

Zhang

Bao

2022

Critical Reviews in Biochemistry and Molecular Biology

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Editorial Overview: Single-Molecule Approaches to Difficult Challenges in Folding and Dynamics

Cited by 3 publications

References 30 publications

A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism

A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism

Single-molecule studies of amyloid proteins: from biophysical properties to diagnostic perspectives

Energetics, kinetics, and pathways of SNARE assembly in membrane fusion

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