Cited by 216Protein Structure and DynamicsForce Microscopy Techniques and ApplicationsHealthcare Operations and Scheduling Optimization

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Non-attendance at general practices and outpatient clinics: Local systems are needed to address local problems

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Sharp, Deborah J, Hamilton, William·2001·BMJ

DOI 10.1136/bmj.323.7321.1081PMC PMC1121587

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Abstract

Abstract Tandem-repeat proteins comprise small secondary structure motifs that stack to form one-dimensional arrays with distinctive mechanical properties that are proposed to direct their cellular functions. Here, we use single-molecule optical tweezers to study the folding of consensus-designed tetratricopeptide repeats (CTPRs) — superhelical arrays of short helix-turn-helix motifs. We find that CTPRs display a spring-like mechanical response in which individual repeats undergo rapid equilibrium fluctuations between folded and unfolded conformations. We rationalise the force response using Ising models and dissect the folding pathway of CTPRs under mechanical load, revealing how the repeat arrays form from the centre towards both termini simultaneously. Strikingly, we also directly observe the protein’s superhelical tertiary structure in the force signal. Using protein engineering, crystallography and single-molecule experiments, we show how the superhelical geometry can be altered by carefully placed amino-acid substitutions and examine how these sequence changes affect intrinsic repeat stability and inter-repeat coupling. Our findings provide the means to dissect and modulate repeat-protein stability and dynamics, which will be essential for researchers to understand the function of natural repeat proteins and to exploit artificial repeats proteins in nanotechnology and biomedical applications. Significance statement Repetition of biological building blocks is crucial to modulating and diversifying structure and function of biomolecules across all organisms. In tandem-repeat proteins, the linear arrangement of small structural motifs leads to the formation of striking supramolecular shapes. Using a combination of single-molecule biophysical techniques and modelling approaches, we dissect the spring-like nature of a designed repeat protein and demonstrate how its shape and mechanics can be manipulated by design. These novel insights into the biomechanical and biochemical characteristics of this protein class give us a methodological basis from which to understand the biological functions of repeat proteins and to exploit them in nanotechnology and biomedicine.

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“Patients who cancel appointments tend to be younger [12,14,15] and of lower socioeconomic status.”
Background
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Authors: Sharp, D. J., & Hamilton, W.
Affiliations: University of Bristol (GB)
Corresponding author: Hamilton, William
ORCID: Hamilton, William
Venue: BMJ
Publisher: BMJ
Published: 2001-11-10
Volume: 323
Issue: 7321
Pages: 1081-1082
ISSN: 0007-1447 (ISSN-L)
0959-8138
1468-5833
DOI: 10.1136/bmj.323.7321.1081
PMC: PMC1121587
OpenAlex: W2093063118
Cited by: 216
References: 10
Citations by year: 2026: 2 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 13 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 15 · 2017: 12 · 2016: 8 · 2015: 11 · 2014: 17 · 2013: 7 · 2012: 17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.bmj.com/company/legal-information/terms-conditions/legal-information/tdm-licencepolicy (tdm)
Locations: BMJ (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Force Microscopy Techniques and Applications
Social Sciences › Decision Sciences › Management Science and Operations Research › Healthcare Operations and Scheduling Optimization
Keywords: non-attendance, general practice, outpatient clinics, health care access, patient attendance
MeSH terms: Appointments and Schedules, Family Practice, United Kingdom, Humans, Outpatient Clinics, Hospital, Patient Acceptance of Health Care, Patient Dropouts

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Non-attendance at general practices and outpatient clinics: Local systems are needed to address local problems

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