{"title":"Looping the Genome with SMC Complexes.","authors":"Eugene Kim, Roman Barth, Cees Dekker","doi":"10.1146/annurev-biochem-032620-110506","DOIUrl":"https://doi.org/10.1146/annurev-biochem-032620-110506","url":null,"abstract":"<p><p>SMC (structural maintenance of chromosomes) protein complexes are an evolutionarily conserved family of motor proteins that hold sister chromatids together and fold genomes throughout the cell cycle by DNA loop extrusion. These complexes play a key role in a variety of functions in the packaging and regulation of chromosomes, and they have been intensely studied in recent years. Despite their importance, the detailed molecular mechanism for DNA loop extrusion by SMC complexes remains unresolved. Here, we describe the roles of SMCs in chromosome biology and particularly review in vitro single-molecule studies that have recently advanced our understanding of SMC proteins. We describe the mechanistic biophysical aspects of loop extrusion that govern genome organization and its consequences.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"15-41"},"PeriodicalIF":16.6,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9725135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Design and Application of DNA-Editing Enzymes as Base Editors.","authors":"Kartik L Rallapalli, Alexis C Komor","doi":"10.1146/annurev-biochem-052521-013938","DOIUrl":"10.1146/annurev-biochem-052521-013938","url":null,"abstract":"<p><p>DNA-editing enzymes perform chemical reactions on DNA nucleobases. These reactions can change the genetic identity of the modified base or modulate gene expression. Interest in DNA-editing enzymes has burgeoned in recent years due to the advent of clustered regularly interspaced short palindromic repeat-associated (CRISPR-Cas) systems, which can be used to direct their DNA-editing activity to specific genomic loci of interest. In this review, we showcase DNA-editing enzymes that have been repurposed or redesigned and developed into programmable base editors. These include deaminases, glycosylases, methyltransferases, and demethylases. We highlight the astounding degree to which these enzymes have been redesigned, evolved, and refined and present these collective engineering efforts as a paragon for future efforts to repurpose and engineer other families of enzymes. Collectively, base editors derived from these DNA-editing enzymes facilitate programmable point mutation introduction and gene expression modulation by targeted chemical modification of nucleobases.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"43-79"},"PeriodicalIF":12.1,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9756297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Inseparable Relationship Between Cholesterol and Hedgehog Signaling.","authors":"Christian Siebold, Rajat Rohatgi","doi":"10.1146/annurev-biochem-052521-040313","DOIUrl":"10.1146/annurev-biochem-052521-040313","url":null,"abstract":"<p><p>Ligands of the Hedgehog (HH) pathway are paracrine signaling molecules that coordinate tissue development in metazoans. A remarkable feature of HH signaling is the repeated use of cholesterol in steps spanning ligand biogenesis, secretion, dispersal, and reception on target cells. A cholesterol molecule covalently attached to HH ligands is used as a molecular baton by transfer proteins to guide their secretion, spread, and reception. On target cells, a signaling circuit composed of a cholesterol transporter and sensor regulates transmission of HH signals across the plasma membrane to the cytoplasm. The repeated use of cholesterol in signaling supports the view that the HH pathway likely evolved by coopting ancient systems to regulate the abundance or organization of sterol-like lipids in membranes.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"273-298"},"PeriodicalIF":12.1,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9769873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Activation Mechanism of the Insulin Receptor: A Structural Perspective.","authors":"Eunhee Choi, Xiao-Chen Bai","doi":"10.1146/annurev-biochem-052521-033250","DOIUrl":"https://doi.org/10.1146/annurev-biochem-052521-033250","url":null,"abstract":"<p><p>The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo-electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including (<i>a</i>) the detailed binding modes and functions of insulin at site 1 and site 2 and (<i>b</i>) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"247-272"},"PeriodicalIF":16.6,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10398885/pdf/nihms-1919378.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9929688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Proteins of mRNA Modification: Writers, Readers, and Erasers.","authors":"Mathieu N Flamand, Matthew Tegowski, Kate D Meyer","doi":"10.1146/annurev-biochem-052521-035330","DOIUrl":"https://doi.org/10.1146/annurev-biochem-052521-035330","url":null,"abstract":"<p><p>Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and erase these marks, with a particular focus on the most abundant internal modification, <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A). We first describe the discovery of the key enzymes that deposit and remove m<sup>6</sup>A and other modifications and discuss how our understanding of these proteins has shaped our views of modification dynamics. We then review current models for the function of m<sup>6</sup>A reader proteins and how our knowledge of these proteins has evolved. Finally, we highlight important future directions for the field and discuss key questions that remain unanswered.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"145-173"},"PeriodicalIF":16.6,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10443600/pdf/nihms-1922506.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10042992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephanie Vrijsen, Marine Houdou, Ana Cascalho, Jan Eggermont, Peter Vangheluwe
{"title":"Polyamines in Parkinson's Disease: Balancing Between Neurotoxicity and Neuroprotection.","authors":"Stephanie Vrijsen, Marine Houdou, Ana Cascalho, Jan Eggermont, Peter Vangheluwe","doi":"10.1146/annurev-biochem-071322-021330","DOIUrl":"https://doi.org/10.1146/annurev-biochem-071322-021330","url":null,"abstract":"<p><p>The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with aging and are altered in patients with PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role of a disturbed polyamine homeostasis in PD. Polyamines affect pathways in PD pathogenesis, such as α-synuclein aggregation, and influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, and lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"435-464"},"PeriodicalIF":16.6,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9662523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Translation and mRNA Stability Control.","authors":"Qiushuang Wu, Ariel A Bazzini","doi":"10.1146/annurev-biochem-052621-091808","DOIUrl":"10.1146/annurev-biochem-052621-091808","url":null,"abstract":"<p><p>Messenger RNA (mRNA) stability and translational efficiency are two crucial aspects of the post-transcriptional process that profoundly impact protein production in a cell. While it is widely known that ribosomes produce proteins, studies during the past decade have surprisingly revealed that ribosomes also control mRNA stability in a codon-dependent manner, a process referred to as codon optimality. Therefore, codons, the three-nucleotide words read by the ribosome, have a potent effect on mRNA stability and provide cis<i>-</i>regulatory information that extends beyond the amino acids they encode. While the codon optimality molecular mechanism is still unclear, the translation elongation rate appears to trigger mRNA decay. Thus, transfer RNAs emerge as potential master gene regulators affecting mRNA stability. Furthermore, while few factors related to codon optimality have been identified in yeast, the orthologous genes in vertebrates do not necessary share the same functions. Here, we discuss codon optimality findings and gene regulation layers related to codon composition in different eukaryotic species.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"92 ","pages":"227-245"},"PeriodicalIF":12.1,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9668847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kami Ahmad, Steven Henikoff, Srinivas Ramachandran
{"title":"Managing the Steady State Chromatin Landscape by Nucleosome Dynamics.","authors":"Kami Ahmad, Steven Henikoff, Srinivas Ramachandran","doi":"10.1146/annurev-biochem-032620-104508","DOIUrl":"10.1146/annurev-biochem-032620-104508","url":null,"abstract":"<p><p>Gene regulation arises out of dynamic competition between nucleosomes, transcription factors, and other chromatin proteins for the opportunity to bind genomic DNA. The timescales of nucleosome assembly and binding of factors to DNA determine the outcomes of this competition at any given locus. Here, we review how these properties of chromatin proteins and the interplay between the dynamics of different factors are critical for gene regulation. We discuss how molecular structures of large chromatin-associated complexes, kinetic measurements, and high resolution mapping of protein-DNA complexes in vivo set the boundary conditions for chromatin dynamics, leading to models of how the steady state behaviors of regulatory elements arise.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"91 ","pages":"183-195"},"PeriodicalIF":12.1,"publicationDate":"2022-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10277172/pdf/nihms-1814593.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10019043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure and Mechanism of the Lipid Flippase MurJ.","authors":"Alvin C Y Kuk, Aili Hao, Seok-Yong Lee","doi":"10.1146/annurev-biochem-040320-105145","DOIUrl":"https://doi.org/10.1146/annurev-biochem-040320-105145","url":null,"abstract":"<p><p>Biosynthesis of many important polysaccharides (including peptidoglycan, lipopolysaccharide, and <i>N</i>-linked glycans) necessitates the transport of lipid-linked oligosaccharides (LLO) across membranes from their cytosolic site of synthesis to their sites of utilization. Much of our current understanding of LLO transport comes from genetic, biochemical, and structural studies of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) superfamily protein MurJ, which flips the peptidoglycan precursor lipid II. MurJ plays a pivotal role in bacterial cell wall synthesis and is an emerging antibiotic target. Here, we review the mechanism of LLO flipping by MurJ, including the structural basis for lipid II flipping and ion coupling. We then discuss inhibition of MurJ by antibacterials, including humimycins and the phage M lysis protein, as well as how studies on MurJ could provide insight into other flippases, both within and beyond the MOP superfamily.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"91 ","pages":"705-729"},"PeriodicalIF":16.6,"publicationDate":"2022-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108830/pdf/nihms-1871783.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9701467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melinda M Diver, John V Lin King, David Julius, Yifan Cheng
{"title":"Sensory TRP Channels in Three Dimensions.","authors":"Melinda M Diver, John V Lin King, David Julius, Yifan Cheng","doi":"10.1146/annurev-biochem-032620-105738","DOIUrl":"10.1146/annurev-biochem-032620-105738","url":null,"abstract":"<p><p>Transient receptor potential (TRP) ion channels are sophisticated signaling machines that detect a wide variety of environmental and physiological signals. Every cell in the body expresses one or more members of the extended TRP channel family, which consists of over 30 subtypes, each likely possessing distinct pharmacological, biophysical, and/or structural attributes. While the function of some TRP subtypes remains enigmatic, those involved in sensory signaling are perhaps best characterized and have served as models for understanding how these excitatory ion channels serve as polymodal signal integrators. With the recent resolution revolution in cryo-electron microscopy, these and other TRP channel subtypes are now yielding their secrets to detailed atomic analysis, which is beginning to reveal structural underpinnings of stimulus detection and gating, ion permeation, and allosteric mechanisms governing signal integration. These insights are providing a framework for designing and evaluating modality-specific pharmacological agents for treating sensory and other TRP channel-associated disorders.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":"91 ","pages":"629-649"},"PeriodicalIF":12.1,"publicationDate":"2022-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9233036/pdf/nihms-1809634.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9702300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}