Related Experiment Video

Updated: May 19, 2026

Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity

Tiancheng Chen1, Krista K Alexander2, Juliana A Martinez Fiesco3

  • 1Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Bioorganic Chemistry
|May 17, 2026
PubMed

Insights

New peptides targeting the C-terminal helix of Leucine-rich repeat kinase 2 (LRRK2) inhibit its activity, offering a novel therapeutic strategy for Parkinson's disease (PD) without altering LRRK2 localization.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD).
  • Pathogenic LRRK2 mutations increase kinase activity, contributing to PD pathology.
  • Mechanisms regulating LRRK2 kinase activation by its domains are not fully understood.

Purpose of the Study:

  • To investigate the role of the LRRK2 C-terminal helix in modulating kinase activity.
  • To develop novel inhibitors targeting LRRK2 C-terminal helix for PD treatment.

Main Methods:

  • Development of cell-penetrant, hydrocarbon-constrained peptides mimicking the LRRK2 C-terminal helix.
  • Assessment of peptide binding to LRRK2 and inhibition of kinase function.
  • Evaluation of peptide effects on LRRK2-associated pathological phenotypes (e.g., centrosomal and ciliary defects) and LRRK2 localization.

Main Results:

  • The developed peptides directly bind to LRRK2 and inhibit its kinase activity.
  • These peptides suppress downstream pathological phenotypes associated with LRRK2.
  • Unlike ATP-competitive inhibitors, these peptides do not cause LRRK2 mislocalization.

Conclusions:

  • The LRRK2 C-terminal helix plays a critical regulatory role in kinase activity.
  • These peptides represent a novel, non-mislocalizing strategy for inhibiting pathogenic LRRK2 in Parkinson's disease.
Keywords:
Constrained peptideKinaseLRRK2Parkinson's diseaseStapled peptide

More Related Videos

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate11:31

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate

Published on: September 18, 2013

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag08:55

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

Published on: December 14, 2017

Related Concept Videos

Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...