Leucine-Rich Repeat Kinases
We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.PMID:38621236 | DOI:10.1146/annurev-biochem-030122-051144 (Source: Annual Review of Biochemistry)
Source: Annual Review of Biochemistry - April 15, 2024 Category: Biochemistry Authors: Dario R Alessi Suzanne R Pfeffer Source Type: research
Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-030122-033754. Online ahead of print.ABSTRACTAlmost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a β-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the β-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis ...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Matthew Thomas Doyle Harris D Bernstein Source Type: research
The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-092823-113814. Online ahead of print.ABSTRACTLysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discu...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Uche N Medoh Monther Abu-Remaileh Source Type: research
Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-030122-033754. Online ahead of print.ABSTRACTAlmost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a β-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the β-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis ...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Matthew Thomas Doyle Harris D Bernstein Source Type: research
The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-092823-113814. Online ahead of print.ABSTRACTLysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discu...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Uche N Medoh Monther Abu-Remaileh Source Type: research
Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-030122-033754. Online ahead of print.ABSTRACTAlmost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a β-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the β-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis ...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Matthew Thomas Doyle Harris D Bernstein Source Type: research
The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-092823-113814. Online ahead of print.ABSTRACTLysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discu...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Uche N Medoh Monther Abu-Remaileh Source Type: research
Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-030122-033754. Online ahead of print.ABSTRACTAlmost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a β-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the β-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis ...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Matthew Thomas Doyle Harris D Bernstein Source Type: research
The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Annu Rev Biochem. 2024 Apr 11. doi: 10.1146/annurev-biochem-092823-113814. Online ahead of print.ABSTRACTLysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discu...
Source: Annual Review of Biochemistry - April 11, 2024 Category: Biochemistry Authors: Uche N Medoh Monther Abu-Remaileh Source Type: research
A Cool Look at Positive-Strand RNA Virus Replication Organelles: New Insights from Cryo-Electron Microscopy
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-052521-115736. Online ahead of print.ABSTRACTPositive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host membranes, transformed into distinct structures such as invaginated spherules or intricate membrane networks including single- and/or double-membrane vesicles. ROs play a vital role in orchestrating viral RNA synthesis and evading detection by innate immune sensors of the hos...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Nina L de Beijer Eric J Snijder Montserrat B árcena Source Type: research
The Story of RNA Unfolded: The Molecular Function of DEAD- and DExH-Box ATPases and Their Complex Relationship with Membraneless Organelles
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-052521-121259. Online ahead of print.ABSTRACTDEAD- and DExH-box ATPases (DDX/DHXs) are abundant and highly conserved cellular enzymes ubiquitously involved in RNA processing. By remodeling RNA-RNA and RNA-protein interactions, they often function as gatekeepers that control the progression of diverse RNA maturation steps. Intriguingly, most DDX/DHXs localize to membraneless organelles (MLOs) such as nucleoli, nuclear speckles, stress granules, or processing bodies. Recent findings suggest not only that localization to MLOs can promote interaction between DDX/DHXs a...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Kerstin D örner Maria Hondele Source Type: research
The Art and Science of Molecular Docking
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-030222-120000. Online ahead of print.ABSTRACTMolecular docking has become an essential part of a structural biologist's and medicinal chemist's toolkits. Given a chemical compound and the three-dimensional structure of a molecular target-for example, a protein-docking methods fit the compound into the target, predicting the compound's bound structure and binding energy. Docking can be used to discover novel ligands for a target by screening large virtual compound libraries. Docking can also provide a useful starting point for structure-based ligand optimization or ...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Joseph M Paggi Ayush Pandit Ron O Dror Source Type: research
The Endo-Lysosomal Damage Response
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-030222-102505. Online ahead of print.ABSTRACTLysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Hemmo Meyer Bojana Kravic Source Type: research
Replication and Transcription of Human Mitochondrial DNA
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-052621-092014. Online ahead of print.ABSTRACTMammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiatio...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Maria Falkenberg Nils-G öran Larsson Claes M Gustafsson Source Type: research
Replication-Transcription Conflicts: A Perpetual War on the Chromosome
Annu Rev Biochem. 2024 Apr 9. doi: 10.1146/annurev-biochem-030222-115809. Online ahead of print.ABSTRACTDNA replication and transcription occur in all living cells across all domains of life. Both essential processes occur simultaneously on the same template, leading to conflicts between the macromolecular machines that perform these functions. Numerous studies over the past few decades demonstrate that this is an inevitable problem in both prokaryotic and eukaryotic cells. We have learned that conflicts lead to replication fork reversal, breaks in the DNA, R-loop formation, topological stress, and mutagenesis, and they ca...
Source: Annual Review of Biochemistry - April 10, 2024 Category: Biochemistry Authors: Kaitlyn R Browning Houra Merrikh Source Type: research
