Biology subjects

Mi, L.-Z.

Publications and source records attributed to Mi, L.-Z..

3 recordsLinked to original sources

bioRxiv2026

DYNAMIC CONFORMATIONS IN THE ACTIVATION OF PINK1 KINASE

Under mitochondrial stress, the mitochondrial kinase PINK1 is activated to phosphorylate ubiquitin, which in turn recruits the E3 ligase Parkin, thereby initiating clearance of damaged mitochondria. Dysregulation of the PINK1-Parkin signaling pathway is associated with early-onset autosomal recessive Parkinson's disease. However, the mechanisms governing PINK1 conformational dynamics and activation in response to mitochondrial stress remain poorly understood. Here, we report that Tribolium castaneum PINK1 (TcPINK1) forms specific symmetric dimers via interactions between the kinase N-lobe and the regulatory C-terminal domain. These dimers undergo dynamic conformational transitions across distinct states, including an autoinhibited state, an inactive intermediate state, a primed-activation state and an active state. Moreover, TcPINK1 undergoes lateral trans-phosphorylation through dimer-dimer interactions. Notably, symmetric dimer formation is essential for Parkin recruitment during mitophagy. These findings provide a framework for understanding the conformational plasticity and allosteric regulation of PINK1 in mitophagy.

biophysics↗

bioRxiv2026

MOLECULAR BASIS FOR PINK1 MATURATION

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a key regulator of mitophagy, has been linked to the pathogenesis of Parkinson's disease (PD). PINK1 recruits Parkin, an E3 ubiquitin ligase, triggering mitophagy in response to mitochondrial damage. During mitophagy, the quantity, stability, and activity of PINK1 must be strictly regulated; however, the mechanisms governing these parameters under cellular stress are still unclear. Herein, we determined the structural basis for PINK1 maturation mediated by heat shock protein 90/cell division cycle 37/FK506-binding protein 51 (HSP90/CDC37/FKBP51) chaperone complex. We identified PINK1-associated proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and determined the structures of the complexes using Cryo-Electron Microscopy (Cryo-EM). Results showed that FKBP51 potentially interacts with a conserved leucine-proline-phenylalanine (LPF) motif on the activation loop of PINK1 and negatively regulates PINK1 functions in mitophagy. A PINK1 mutation located at the FKBP51 recognition site is linked to mitophagy deficiency, which can be partially rescued by specific inhibition of FKBP51. These findings reveal a general mechanism for PINK1 recognition by the HSP90/CDC37/FKBP51 chaperone complex and suggest a potential approach for upregulating PINK1 activity, which is impaired in PD.

biophysics↗

bioRxiv2024

Multiple allostery in the regulation of PDGFR beta kinase activities

Platelet-derived growth factor receptor beta (PDGFR{beta}), a type III receptor tyrosine kinase (RTK) with a featured kinase insert, regulates important cellular functions. Dysregulation of PDGFR{beta} is associated with cardiovascular and fibrosis diseases. Thus, its kinase activity needs to be precisely regulated under physiological conditions. Early studies demonstrated that its kinase was autoinhibited by its juxtamembrane segment and activated by transphosphorylation. However, additional mechanisms are required for the comprehensive regulation of the receptor kinase. Herein, we provide evidences that dimerization of activated kinases, autoinhibition by the kinase insert, and dimerization of inactive kinase, all contribute to the regulation of the receptor kinase. Moreover, we find such multiple allosteric regulation is also conserved in other type III RTKs, including colony stimulating factor 1 receptor (CSF1R). Impairing the allosteric regulation of CSF1R is associated with malfunctions of microglia and demyelination of neurons in Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS).

biophysics↗