Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

How small peptides block and reverse serpin polymerisation.

Aiwu Zhou1, Penelope E Stein, James A Huntington

  • 1Departments of Haematology and Medicine, University of Cambridge, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK.

Journal of Molecular Biology
|September 3, 2004
PubMed
Summary
This summary is machine-generated.

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

How much Copper Do Calves Need? Retention and Hepatic Storage in Artificially Reared Milk-Fed Holstein-Friesian Calves.

Biological trace element research·2026
Same author

Elastic rebound engineering via leaf venation mimicry: boosting droplet spreading for high-performance triboelectric nanogenerators.

Microsystems & nanoengineering·2026
Same author

Guidelines for the management of acute porphyria: recommendations from the International Porphyria Network.

The Lancet. Haematology·2026
Same author

BMN 349, a small molecule inhibitor of Z alpha-1 antitrypsin polymerization, increases secretion and reduces intrahepatic inclusions in a mouse model of disease.

Hepatology (Baltimore, Md.)·2026
Same author

Prothrombinase processivity is conferred by substrate allostery.

The EMBO journal·2026
Same author

Z variant heterozygosity in alpha-1 antitrypsin deficiency: disease risk and treatment implications.

Orphanet journal of rare diseases·2026
Same journal

UPF3A and UPF3B shape the transcriptome cooperatively yet oppose cell function.

Journal of molecular biology·2026
Same journal

Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis.

Journal of molecular biology·2026
Same journal

Small molecule stabilization of diverse amyloidogenic immunoglobulin light chains revealed by hydrogen-deuterium exchange mass spectrometry.

Journal of molecular biology·2026
Same journal

UPF1 at Work: Structural and Mechanistic Insights Into a Master Regulator of Nonsense-Mediated mRNA Decay.

Journal of molecular biology·2026
Same journal

Structural basis for the pro-amyloidogenic action and ligand binding of a novel W72R variant of human apolipoprotein A-I.

Journal of molecular biology·2026
Same journal

Cryo-EM Structure of the C. Elegans Septin Tetramer Reveals a Revised Architecture and Conserved Positional Orthology.

Journal of molecular biology·2026
See all related articles

Researchers identified structural requirements for small peptides to block pathological protein aggregation, a cause of dementia and other diseases. This discovery enables the rational design of synthetic peptides to prevent disease-associated polymer formation.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Aberrant protein aggregation causes late-onset dementias like Alzheimer's disease and prion encephalopathies.
  • The serpin family of serine protease inhibitors exemplifies pathological aggregation, with mutant variants forming polymers linked via the reactive site loop inserting into the s4A beta-sheet.
  • This aggregation mechanism underlies diseases including thrombosis and dementia.

Purpose of the Study:

  • To define the structural requirements for small peptides to competitively bind and block the s4A position.
  • To prevent the intermolecular linkage and polymerization of serpin proteins.
  • To enable the rational design of synthetic blocking peptides for therapeutic applications.

Main Methods:

  • X-ray crystallography was used to determine the structures of complexes formed between blocking peptides and serpin.

Related Experiment Videos

  • Analysis of peptide-protein interactions to identify key binding sites and molecular interactions.
  • Design and synthesis of novel blocking peptides based on identified structural requirements.

    • Main Results:

    • Small peptides can competitively bind to and block the s4A position, preventing serpin polymerization.
    • A threonine residue in blocking peptides facilitates entry and anchoring into the P8 equivalent site of s4A.
    • Hydrophobic side-chains of peptides binding to the P4 and P6 sites of s4A are critical for stable complex formation.
    • A rationally designed tetrapeptide demonstrated preferential blocking of a pathologically unstable serpin variant.

    Conclusions:

    • The study elucidates the structural basis for blocking pathological serpin polymerization.
    • Findings facilitate the rational design of small, synthetic peptides for therapeutic intervention in protein misfolding diseases.
    • The developed tetrapeptide shows promise for preventing polymerization of disease-associated serpin variants.