scholarly journals AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy

2021 ◽  
Vol 7 (15) ◽  
pp. eabg4544
Author(s):  
Chien-Min Hung ◽  
Portia S. Lombardo ◽  
Nazma Malik ◽  
Sonja N. Brun ◽  
Kristina Hellberg ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Phosphorylation Sites ◽  
Serine Threonine Kinase ◽  
Early Step ◽  
Threonine Kinase ◽  
The Core ◽  
Act Domain ◽  
Genetic Deletion ◽  
Cellular Stresses ◽  
Familial Parkinson’S Disease

The serine/threonine kinase ULK1 mediates autophagy initiation in response to various cellular stresses, and genetic deletion of ULK1 leads to accumulation of damaged mitochondria. Here we identify Parkin, the core ubiquitin ligase in mitophagy, and PARK2 gene product mutated in familial Parkinson’s disease, as a ULK1 substrate. Recent studies uncovered a nine residue (“ACT”) domain important for Parkin activation, and we demonstrate that AMPK-dependent ULK1 rapidly phosphorylates conserved serine108 in the ACT domain in response to mitochondrial stress. Phosphorylation of Parkin Ser108 occurs maximally within five minutes of mitochondrial damage, unlike activation of PINK1 and TBK1, which is observed thirty to sixty minutes later. Mutation of the ULK1 phosphorylation sites in Parkin, genetic AMPK or ULK1 depletion, or pharmacologic ULK1 inhibition, all lead to delays in Parkin activation and defects in assays of Parkin function and downstream mitophagy events. These findings reveal an unexpected first step in the mitophagy cascade.

New insights into PKC family affairs: three novel phosphorylation sites in PKCϵ and at least one is regulated by PKCα

2008 ◽  
Vol 411 (2) ◽  
pp. e15-e16 ◽  
Author(s):  
Christer Larsson
Keyword(s):  
Phosphorylation Sites ◽  
Functional Importance ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Biochemical Journal ◽  
Pkc Isoforms ◽  
Evolutionarily Conserved ◽  
The Individual

PKCϵ (protein kinase Cϵ) is a serine/threonine kinase, and a member of the PKC family of isoforms. The different PKC isoforms regulate many cellular processes of importance for disease. It is therefore desirable to obtain tools to specifically modulate the activity of the individual isoforms and to develop markers of PKC activity. The paper by Durgan et al. in this issue of the Biochemical Journal has taken us some steps further towards these goals. In the paper they identify three previously unknown phosphorylation sites in PKCϵ. All of them are specific for the ϵ isoform, evolutionarily conserved and tightly regulated. The phosphorylation of one site is critical for the binding of PKCϵ to 14-3-3β, suggesting it is of functional importance. The results provide important novel findings that uncover new aspects of PKCϵ regulation and reveal new possibilities for detecting PKCϵ activity in situ.

The endoplasmic reticulum/mitochondria interface: a subcellular platform for the orchestration of the functions of the PINK1–Parkin pathway?

2015 ◽  
Vol 43 (2) ◽  
pp. 297-301 ◽  
Author(s):  
Zoi Erpapazoglou ◽  
Olga Corti
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Serine Threonine Kinase ◽  
Subcellular Compartment ◽  
Ubiquitin Protein Ligase ◽  
Threonine Kinase ◽  
Parkinsonian Syndromes ◽  
Phosphatase And Tensin Homologue ◽  
Familial Parkinson’S Disease

Mitochondrial dysfunction is a hallmark of both idiopathic and familial Parkinson's disease (PD). Mutations in the PARK2 and PARK6 genes, coding for the cytosolic E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1], lead to clinically similar early-onset Parkinsonian syndromes. PINK1 and Parkin cooperate within a conserved pathway to preserve mitochondrial quality through the regulation of a variety of processes, including mitochondrial dynamics, transport, bioenergetics, biogenesis and turnover. The molecular mechanisms behind the orchestration of this plethora of functions remain poorly understood. In the present review, we emphasize the functional overlap between the PINK1–Parkin pathway and the endoplasmic reticulum (ER)-mitochondria interface, a subcellular compartment critically involved in neurodegeneration. We discuss how this compartment may constitute a hub for the spatiotemporal organization of the activities of the PINK1–Parkin pathway.

TheMycobacterium tuberculosis serine/threonine kinase PknL phosphorylates Rv2175c: Mass spectrometric profiling of the activation loop phosphorylation sites and their role in the recruitment of Rv2175c

PROTEOMICS ◽  
2008 ◽  
Vol 8 (3) ◽  
pp. 521-533 ◽  
Author(s):  
Marc J. Canova ◽  
Romain Veyron-Churlet ◽  
Isabelle Zanella-Cleon ◽  
Martin Cohen-Gonsaud ◽  
Alain J. Cozzone ◽  
...  
Keyword(s):  
Mass Spectrometric ◽  
Activation Loop ◽  
Phosphorylation Sites ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

scholarly journals Ubiquitin Hydrolase UCH-L1 Destabilizes mTOR Complex 1 by Antagonizing DDB1-CUL4-Mediated Ubiquitination of Raptor

2013 ◽  
Vol 33 (6) ◽  
pp. 1188-1197 ◽  
Author(s):  
Sajjad Hussain ◽  
Andrew L. Feldman ◽  
Chittaranjan Das ◽  
Steven C. Ziesmer ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Biological Functions ◽  
Serine Threonine Kinase ◽  
Normal Cells ◽  
S6 Kinase ◽  
Threonine Kinase ◽  
Ubiquitin Ligase Complex ◽  
Mtor Complex 1

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates processes including mRNA translation, proliferation, and survival. By assembling with different cofactors, mTOR forms two complexes with distinct biological functions. Raptor-bound mTOR (mTORC1) governs cap-dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative kinase Akt. How the balance between the competing needs for mTORC1 and -2 is controlled in normal cells and deregulated in disease is poorly understood. Here, we show that the ubiquitin hydrolase UCH-L1 regulates the balance of mTOR signaling by disrupting mTORC1. We find that UCH-L1 impairs mTORC1 activity toward S6 kinase and 4EBP1 while increasing mTORC2 activity toward Akt. These effects are directly attributable to a dramatic rearrangement in mTOR complex assembly. UCH-L1 disrupts a complex between the DDB1-CUL4 ubiquitin ligase complex and raptor and counteracts DDB1-CUL4-mediated raptor ubiquitination. These events lead to mTORC1 dissolution and a secondary increase in mTORC2. Experiments inUchl1-deficient and transgenic mice suggest that the balance between these pathways is important for preventing neurodegeneration and the development of malignancy. These data establish UCH-L1 as a key regulator of the dichotomy between mTORC1 and mTORC2 signaling.

Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis

2008 ◽  
Vol 415 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Meghna Thakur ◽  
Pradip K. Chakraborti
Keyword(s):  
Protein Kinases ◽  
Solid Phase ◽  
Morphological Changes ◽  
Binding Assays ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Peptidoglycan Biosynthesis ◽  
Vitro Binding ◽  
Solid Phase Binding

Eukaryotic-type serine/threonine protein kinases in bacteria have been implicated in controlling a host of cellular activities. PknA is one of eleven such protein kinases from Mycobacterium tuberculosis which regulates morphological changes associated with cell division. In the present study we provide the evidence for the ability of PknA to transphosphorylate mMurD (mycobacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate-ligase), the enzyme involved in peptidoglycan biosynthesis. Its co-expression in Escherichia coli along with PknA resulted in phosphorylation of mMurD. Consistent with these observations, results of the solid-phase binding assays revealed a high-affinity in vitro binding between the two proteins. Furthermore, overexpression of m-murD in Mycobacterium smegmatis yielded a phosphorylated protein. The results of the present study therefore point towards the possibility of mMurD being a substrate of PknA.

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