Biochemistry Biochemistry最新文献

{"title":"Structural Elucidation of the Reduced Mn(III)/Fe(III) Intermediate of the Radical-Initiating Metallocofactor in Chlamydia trachomatis Ribonucleotide Reductase","authors":"Ryan J. Martinie*,&nbsp;Jovan Livada,&nbsp;Nyaari Kothiya,&nbsp;J. Martin Bollinger Jr.,&nbsp;Carsten Krebs and Alexey Silakov*,&nbsp;","doi":"10.1021/acs.biochem.4c0069210.1021/acs.biochem.4c00692","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00692https://doi.org/10.1021/acs.biochem.4c00692","url":null,"abstract":"<p >Ribonucleotide reductases (RNRs) are the sole <i>de novo</i> source of deoxyribonucleotides for DNA synthesis and repair across all organisms and carry out their reaction via a radical mechanism. RNR from <i>Chlamydia trachomatis</i> generates its turnover-initiating cysteinyl radical by long-range reduction of a Mn(IV)/Fe(III) cofactor, producing a Mn(III)/Fe(III) intermediate. Herein, we characterize the protonation states of the inorganic ligands in this reduced state using advanced pulse electron paramagnetic resonance (EPR) spectroscopy and ²H-isotope labeling. A strongly coupled deuteron is observed by hyperfine sublevel correlation (HYSCORE) spectroscopy experiments and indicates the presence of a bridging hydroxo ligand. Isotope-dependent EPR line broadening analysis and the magnitude of the estimated Mn–Fe exchange coupling constant together suggest a μ-oxo/μ-hydroxo core. Two distinct signals detected in electron–nuclear double resonance (ENDOR) spectra are attributable to less strongly coupled hydrons of a terminal water ligand to Mn(III). Together, these experiments imply that the reduced cofactor has a mixed μ-oxo/μ-hydroxo core with a terminal water ligand on Mn(III). This structural assignment sheds light generally on the reactivity of Mn/Fe heterobimetallic sites and, more specifically, on the proton-coupling in the electron transfer that initiates ribonucleotide reduction in this subclass of RNRs.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1157–1167 1157–1167"},"PeriodicalIF":2.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.4c00692","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein and DNA Conformational Changes Contribute to Specificity of Cre Recombinase","authors":"Jonathan S. Montgomery,&nbsp;Megan E. Judson and Mark P. Foster*,&nbsp;","doi":"10.1021/acs.biochem.4c0084110.1021/acs.biochem.4c00841","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00841https://doi.org/10.1021/acs.biochem.4c00841","url":null,"abstract":"<p >Cre, a conservative site-specific tyrosine recombinase, is a powerful gene editing tool in the laboratory. Expanded applications in human health are hindered by a lack of understanding of the mechanism by which Cre selectively binds and recombines its cognate <i>loxP</i> sequences. This knowledge is essential for retargeting the enzyme to new sites and for mitigating the effects of off-target recombination. Prior studies have suggested that in addition to a few base-specific contacts to cognate <i>loxP</i> DNA, the enzyme’s specificity is enhanced by (1) autoinhibition involving a conformational change in the protein’s C-terminal helix and (2) indirect readout via binding-coupled conformational changes in the target DNA. We used isothermal titration calorimetry (ITC), circular dichroism (CD), and heteronuclear NMR spectroscopy to investigate DNA site recognition by wild-type Cre and a deletion mutant lacking the C-terminal helix. ITC of Cre and a C-terminal deletion variant against cognate and noncognate DNA recombinase binding elements (RBEs) reveal that the C-terminus reduces DNA binding affinity by 6-fold toward cognate DNA. Additionally, ITC revealed highly unfavorable binding enthalpy, which, when combined with evidence from CD and NMR of structural differences between cognate and noncognate complexes, supports a model in which binding-coupled DNA bending provides a unique structure-thermodynamic signature of cognate complexes. Together, these findings advance our understanding of site recognition by Cre recombinase.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1055–1064 1055–1064"},"PeriodicalIF":2.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and Engineering of a Blue-Sensitive, Gi/o-Biased, and Bistable Ciliary Opsin from a Fan Worm","authors":"Sachiko Fukuzawa,&nbsp;Tomoki Kawaguchi,&nbsp;Takushi Shimomura,&nbsp;Yoshihiro Kubo and Hisao Tsukamoto*,&nbsp;","doi":"10.1021/acs.biochem.4c0075410.1021/acs.biochem.4c00754","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00754https://doi.org/10.1021/acs.biochem.4c00754","url":null,"abstract":"<p >Ciliary opsins (c-opsin) have been identified not only in vertebrates but also in invertebrates. An invertebrate ciliary opsin was recently identified in the fan worm <i>Acromegalomma interruptum</i> (formerly named <i>Megalomma interrupta</i>); however, its spectral and signaling characteristics are unknown. In the present study, we characterized the spectral properties and light-induced cellular signaling properties of opsin (<i>Acromegalomma</i> invertebrate ciliary opsin (<i>Acr</i>InvC-opsin)). <i>Acr</i>InvC-opsin showed an absorption maximum at 464 nm, and upon blue light absorption, the spectrum was red-shifted by approximately 50 nm. The two states are interconvertible by illumination with blue and orange light. Blue light illumination of <i>Acr</i>InvC-opsin caused specific coupling with Gi, sustained Gi dissociation, decreased intracellular cAMP levels, and the activation of GIRK channels. The cellular responses by the activated opsin were partially terminated by orange light illumination. These light-dependent responses indicate that InvC-opsin is a typical bistable pigment wherein the resting and activated states can be interconverted by visible light illumination. We also attempted to modulate the spectral and functional properties of <i>Acr</i>InvC-opsin by using site-directed mutagenesis. Substitution of Ser-94 with Ala caused little spectral shift in the resting state but a further red shift of ∼10 nm in the activated state, indicating that the absorption spectra of the two states were tuned differently. In contrast, the substitution of S94A did not significantly affect the light-dependent signaling properties of <i>Acr</i>InvC-opsin. Because <i>Acr</i>InvC-opsin is a blue-sensitive, Gi/o-biased, and bistable pigment, it has the potential to serve as an optical control tool to specifically and reversibly regulate Gi/o-dependent signaling pathways by visible light.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1020–1031 1020–1031"},"PeriodicalIF":2.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Binding Mode of TSC2–Rheb through Protein Docking and Simulations","authors":"Berith F. Pape,&nbsp;Shraddha Parate,&nbsp;Leif A. Eriksson* and Vibhu Jha*,&nbsp;","doi":"10.1021/acs.biochem.4c0056210.1021/acs.biochem.4c00562","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00562https://doi.org/10.1021/acs.biochem.4c00562","url":null,"abstract":"<p >Proteasome inhibitors (PIs) constitute the first line of therapy for multiple myeloma (MM). Despite the impressive clinical efficacy, MM remains fatal due to the development of drug resistance over time. During MM progression, stress responses to hypoxia and PIs suppress mammalian target of rapamycin complex 1 (mTORC1) activity by releasing tuberous sclerosis complex 2 (TSC2), which deactivates Ras homologue enriched in brain (Rheb), a crucial regulator of mTORC1. The efficacy of PIs targeting MM is enhanced when mTORC1 is hyperactivated. We thus propose that the inhibition of TSC2 will improve the efficacy of PIs targeting MM. To the best of our knowledge, no cocrystallized structure of the TSC2–Rheb complex has been reported. We therefore developed a representative model using the individual structures of TSC2 (PDB: 7DL2) and Rheb (PDB: 1XTS). Computational modeling involving an extensive protein–protein docking consensus approach was performed to determine the putative binding mode of TSC2–Rheb. The proposed docking poses were refined, clustered, and evaluated by MD simulations to explore the conformational dynamics and protein mobility, particularly at the drug-binding interface of TSC2–Rheb. Our results agree with the suggested binding mode of TSC2–Rheb previously reported in the literature. The results reported herein establish a basis for the development of new inhibitors blocking the binding of TSC2 and Rheb, aiming to reinstate mTORC1 activation and facilitate improved efficacy of PIs against multiple myeloma.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1006–1019 1006–1019"},"PeriodicalIF":2.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.4c00562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Ligands Achieve Biased Signaling toward Arrestins","authors":"Qianru Jiang,&nbsp; and ,&nbsp;Tao Che*,&nbsp;","doi":"10.1021/acs.biochem.4c0084310.1021/acs.biochem.4c00843","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00843https://doi.org/10.1021/acs.biochem.4c00843","url":null,"abstract":"<p >G protein-coupled receptors (GPCRs) mediate the effects of various endogenous and extracellular stimuli through multiple transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. Biased signaling, which preferentially activates certain G protein or GRK/arrestin signaling pathways, provides great opportunities for developing drugs with enhanced therapeutic efficacy and minimized side effects. In this Review, we review studies addressing the structural dynamics of GPCRs bound to balanced and biased ligands and current consensus on how ligand–receptor interactions determine signaling outcomes. We also examine the conformational changes in GPCRs when in complex with G proteins, arrestins, and GRKs, highlighting a more profound impact of signal transducers on receptor rearrangements compared with biased ligands. This evidence supports the idea that biased signaling can be achieved through the promotion of multiple conformational states by biased agonists and the stabilization of specific active conformations by individual signal transducers.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"967–977 967–977"},"PeriodicalIF":2.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Acyl Carrier Protein Docking Sites Help Mediate the Opposite Stereoselectivities of A- and B-type Modular Polyketide Synthase Ketoreductases","authors":"Katherine A. Ray,&nbsp;Sally N. Lin and Adrian T. Keatinge-Clay*,&nbsp;","doi":"10.1021/acs.biochem.4c0056510.1021/acs.biochem.4c00565","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00565https://doi.org/10.1021/acs.biochem.4c00565","url":null,"abstract":"<p >The domains of modular polyketide synthases (PKSs) collaborate to extend and process polyketide intermediates; however, most of their interactions with one another remain mysterious. We used AlphaFold 2 to investigate how acyl carrier proteins (ACPs) present intermediates to ketoreductases (KRs), processing domains capable of not only setting the stereochemical orientations of β-hydroxyl substituents but also of α-substituents. In modules that do not contain a dehydratase (DH), the A- and B-type KRs that, respectively, generate <span>l</span>- and <span>d</span>-oriented β-hydroxy groups are predicted to possess distinct ACP docking sites. In modules containing DHs, where A-type KRs are much less common, both KR types are predicted to possess an ACP-docking site equivalent to that of B-type KRs from modules without DHs. To investigate this most common ACP docking site, mutagenesis was performed on 20 residues of the KR from the second pikromycin module within the model triketide synthase <b>P1</b>-<b>P2</b>-<b>P7</b>. The least active variants are those with mutations to a conserved hydrophobe, 2 residues downstream of the LDD motif of B-type KRs, predicted to insert into a hole adjacent to the phosphopantetheinylated serine of ACP.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1136–1145 1136–1145"},"PeriodicalIF":2.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-Steady-State Kinetic Studies of Nucleotide Incorporation into a Single-Nucleotide Gapped DNA Substrate Catalyzed by Human DNA Polymerase β","authors":"Daniel Betancourt,&nbsp;Turner W. Seay,&nbsp;Nikita Zalenski and Zucai Suo*,&nbsp;","doi":"10.1021/acs.biochem.4c0080410.1021/acs.biochem.4c00804","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00804https://doi.org/10.1021/acs.biochem.4c00804","url":null,"abstract":"<p >DNA polymerase β (Polβ) is a key enzyme in DNA base excision repair (BER). Despite extensive research, several microscopic rate constants within the kinetic mechanism of nucleotide incorporation into single-nucleotide gapped DNA by Polβ have not been determined and the identity of the rate-limiting step remains controversial. Here, we employed pre-steady-state kinetic methods and determined the rate constants for correct dNTP association (<i>k</i>₂ = 4.5 × 10⁶ M^–1 s^–1) and dissociation (<i>k</i>_<i>–</i>2 = 118 s^–1) as well as DNA product release (k₇=0.93 s^–1). Previously, uncertainty regarding the transition state of phosphodiester bond formation has led to confusion regarding the interpretation of the sulfur elemental effect between the incorporations of dNTP and its thio analog <i>S</i>_p-dNTPαS. However, recent results from time-resolved X-ray crystallographic studies of three DNA polymerases have allowed us to revise the benchmark of sulfur elemental effect for a rate-limiting chemistry step from 4–11 to 10–160. By using the revised benchmark, we determined the sulfur elemental effects for correct and incorrect nucleotide incorporation to be 3.94 and 64.6, respectively. These suggest the chemistry step limits mismatched, but not matched, nucleotide incorporation. Furthermore, the 2.1-fold difference in the reaction amplitudes of the pulse-quench and pulse-chase assays provides definitive evidence that a protein conformational change step prior to the chemistry step is rate-limiting for matched nucleotide incorporation. These findings unify the kinetic mechanism of correct nucleotide incorporation for Polβ and all other kinetically characterized DNA polymerases and reverse transcriptases, in which the protein conformational change prior to the chemistry step is rate-limiting.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 5","pages":"1032–1041 1032–1041"},"PeriodicalIF":2.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathway Specific Unbinding Free Energy Profiles of Ritonavir Dissociation from HIV-1 Protease","authors":"Emily Vig,&nbsp;Jianan Sun and Chia-en A. Chang*,&nbsp;","doi":"10.1021/acs.biochem.4c0056010.1021/acs.biochem.4c00560","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00560https://doi.org/10.1021/acs.biochem.4c00560","url":null,"abstract":"<p >Investigation of protein–drug recognition is key to understanding drug selectivity and binding affinity. In combination, the binding/unbinding free energy landscape and intermolecular interactions can be used to understand drug binding/unbinding mechanisms. This information is vital for the development of drugs with improved efficacy and explanation of mutation effects. This study investigated the dissociation processes of ritonavir unbinding from HIV protease (HIVp). Analyzing unbinding trajectories modeled by accelerated molecular dynamics (MD) simulations, three distinct pathways, pathways A–C, were characterized. Using a reduced dimensionality strategy with the principal component analysis, we carried out short classical MD runs with explicit water to sample local fluctuation during ritonavir dissociation and applied the milestoning theory to construct an unbinding free energy landscape. We found that each pathway showed similar values of binding free energy, albeit pathway A accounts for over 50% of dissociation trajectories. Interestingly, residue–residue correlation network analysis showed that in pathway A, a broad correlation network outside the flap region governs protein motions during ritonavir unbinding, which includes residues with reported mutation effects. However, the other two pathways showed limited correlation networks where no reported mutated residues were involved, explaining the favorability of pathway A. Guided by the free energy profile, we investigated each energy barrier and minimum, demonstrating that hydrogen bonding governed movement of the flap regions, directly impacting the calculated energy. Our study provided a new strategy to estimate ligand binding free energy and demonstrated the importance of the transient interactions during ligand–protein dissociation pathways in understanding drug unbinding.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 4","pages":"940–952 940–952"},"PeriodicalIF":2.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conversion of Inactive Non-Pro1 Tautomerase Superfamily Members into Active Tautomerases: Analysis of the Pro1 Mutants","authors":"Emily B. Lancaster,&nbsp;Haley A. Hardtke,&nbsp;Trevor R. Melkonian,&nbsp;Mukesh Venkat Ramani,&nbsp;William H. Johnson Jr,&nbsp;Bert-Jan Baas,&nbsp;Y. Jessie Zhang* and Christian P. Whitman*,&nbsp;","doi":"10.1021/acs.biochem.4c0033810.1021/acs.biochem.4c00338","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00338https://doi.org/10.1021/acs.biochem.4c00338","url":null,"abstract":"<p >Pro1 is a critical catalytic residue in the characterized activities of tautomerase superfamily (TSF) members. Only a handful of members (∼346) lack Pro1 in a sequence similarity network (SSN) that consists of over 11,000 members. Most (294 members) are in the malonate semialdehyde decarboxylase (MSAD)-like subgroup, but the ones characterized thus far have little or no MSAD activity. Moreover, there is little to no activity with other TSF substrates. Five non-Pro1 members were selected randomly for kinetic [using phenylenolpyruvate (PP) and 2-hydroxymuconate (2HM)], mutagenic, inhibition, and crystallographic analysis. Using PP, <i>k</i>_cat/<i>K</i>_m values (∼10¹–10² M^–1 s^–1) could be estimated for three native proteins whereas using 2HM, a <i>k</i>_cat/<i>K</i>_m value could only be estimated for one native protein (∼10³ M^–1 s^–1). The <i>k</i>_cat and <i>K</i>_m values could not be determined. However, changing the N-terminal residue to a proline gave a significant improvement in <i>k</i>_cat/<i>K</i>_m values for all mutant enzymes using PP or 2HM. For PP, the <i>k</i>_cat/<i>K</i>_m values ranged from 10³–10⁵ M^–1 s^–1 and for 2HM, the <i>k</i>_cat/<i>K</i>_m values ranged from 10²–10⁴ M^–1 s^–1. In addition, it was now possible to measure <i>k</i>_cat and <i>K</i>_m values for all mutant proteins using PP and one mutant protein using 2HM. Incubation of the Pro1 mutants with 3-bromopropiolate (3BP) results in covalent modification of the prolyl nitrogen of Pro1 by a 3-oxopropanoate adduct. Crystallographic analysis of two mutant enzymes (NJ7V1P and 8U6S1P) modified by the 3-oxopropanoate adduct identified binding ligands and suggest a mechanism for the tautomerase activity involving Pro1, Arg71, Tyr124, and the backbone amide of Phe68.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 4","pages":"812–822 812–822"},"PeriodicalIF":2.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Huntingtin Transport Complex","authors":"Emily N. P. Prowse,&nbsp;Brooke A. Turkalj,&nbsp;Lale Gursu and Adam G. Hendricks*,&nbsp;","doi":"10.1021/acs.biochem.4c0081110.1021/acs.biochem.4c00811","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00811https://doi.org/10.1021/acs.biochem.4c00811","url":null,"abstract":"<p >A dynamic network of scaffolding molecules, adaptor proteins, and motor proteins work together to orchestrate the movement of proteins, mRNA, and vesicular cargoes. Defects in intracellular transport can often lead to neurodegeneration. Huntingtin (HTT) is a ubiquitously expressed scaffolding protein with a multitude of cellular roles, including regulating the transport of various organelles. HTT is remarkable in its ability to regulate the transport of a wide range of cargoes, including BDNF vesicles, APP vesicles, early endosomes, autophagosomes, lysosomes, and mitochondria. This interaction network allows huntingtin to control microtubule-based transport by kinesin and dynein, as well as actin-based transport by myosin VI. By forming complexes with multiple motor adaptors, huntingtin regulates a variety of cargoes and guides cargoes through the different stages of biosynthesis, signaling, and degradation. Accordingly, pathogenic polyglutamine expansions seen in Huntington’s Disease (HD) dysregulate huntingtin transport complexes, resulting in defects in transport and neurodegeneration.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 4","pages":"760–769 760–769"},"PeriodicalIF":2.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}