Understanding a protein fold: The physics, chemistry, and biology of α-helical coiled coils

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(4), P. 104579 - 104579

Published: March 5, 2023

Protein science is being transformed by powerful computational methods for structure prediction and design: AlphaFold2 can predict many natural protein structures from sequence, other AI are enabling the de novo design of new structures. This raises a question: how much do we understand underlying sequence-to-structure/function relationships captured these methods? perspective presents our current understanding one class assembly, α-helical coiled coils. At first sight, straightforward: sequence repeats hydrophobic (h) polar (p) residues, (hpphppp)n, direct folding assembly amphipathic α helices into bundles. However, different bundles possible: they have two or more (different oligomers); parallel, antiparallel, mixed arrangements topologies); helical sequences be same (homomers) (heteromers). Thus, sequence-to-structure must present within hpphppp to distinguish states. I discuss this problem at three levels: first, physics gives parametric framework generate possible coiled-coil backbone Second, chemistry provides means explore deliver relationships. Third, biology shows coils adapted functionalized in nature, inspiring applications synthetic biology. argue that largely understood; partly solved, though considerable challenge predicting even relative stabilities states remains; but there

Language: Английский

---

Disruption of axonal transport in neurodegeneration

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(11)

Published: May 31, 2023

Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body synapse retrograde signaling endosomes autophagosomes degradation. Dysregulation occurs early in neurodegenerative diseases plays a key role degeneration. Here, we provide an overview mechanisms regulation transport; discuss how these disrupted including Alzheimer’s disease, Parkinson’s Huntington’s hereditary spastic paraplegia, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease; therapeutic approaches targeting transport.

Language: Английский

---

Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 393 - 403

Published: Feb. 22, 2024

Abstract Cells sense physical forces and convert them into electrical or chemical signals, a process known as mechanotransduction. Whereas extensive studies focus on mechanotransduction at the plasma membrane, little is about whether how intracellular organelles mechanical force physiological functions of organellar mechanosensing. Here we identify Drosophila TMEM63 ( Dm TMEM63) ion channel an intrinsic mechanosensor lysosome, major degradative organelle. Endogenous proteins localize to lysosomes, mediate lysosomal mechanosensitivity modulate morphology function. Tmem63 mutant flies exhibit impaired degradation, synaptic loss, progressive motor deficits early death, with some these phenotypes recapitulating symptoms TMEM63-associated human diseases. Importantly, mouse TMEM63A mediates in Neuro-2a cells, indicative functional conservation mammals. Our findings reveal function lysosomes its roles vivo provide molecular basis explore mechanosensitive subcellular organelles.

Language: Английский

---

LRRK2 phosphorylation of Rab GTPases in Parkinson's disease

FEBS Letters, Journal Year: 2022, Volume and Issue: 597(6), P. 811 - 818

Published: Sept. 17, 2022

Rab GTPases comprise a large family of conserved that are critical regulators the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs localize to discrete membrane compartments and, when in their GTP‐bound state, bind effector proteins carry out diverse functions. Activating mutations LRRK2 kinase cause Parkinson's disease, subsets important substrates. phosphorylates threonine residue is essential for interaction with guanine nucleotide exchange factors, effectors, GDI recycles between compartments. This brief review will highlight new findings related LRRK2‐mediated phosphorylation its consequences. Remarkably, flips switch on selection dominant consequences cell pathophysiology.

Language: Английский

---

The Rab5 effector FERRY links early endosomes with mRNA localization

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(11), P. 1839 - 1855.e13

Published: June 1, 2023

Localized translation is vital to polarized cells and requires precise robust distribution of different mRNAs ribosomes across the cell. However, underlying molecular mechanisms are poorly understood important players lacking. Here, we discovered a Rab5 effector, five-subunit endosomal RNA/ribosome intermediary (FERRY) complex, that recruits early endosomes through direct mRNA-interaction. FERRY displays preferential binding certain groups transcripts, including encoding mitochondrial proteins. Deletion subunits reduces localization transcripts in has significant impact on mRNA levels. Clinical studies show genetic disruption causes severe brain damage. We found that, neurons, co-localizes with endosomes, loaded FERRY-positive close proximity mitochondria. thus transforms into carriers plays key role regulating transport.

Language: Английский

---

Aggrephagy at a glance

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(10)

Published: May 15, 2023

ABSTRACT Cells keep their proteome functional by the action of proteostasis network, composed chaperones, ubiquitin-proteasome system and autophagy. The decline this network results in accumulation protein aggregates is associated with aging disease. In Cell Science at a Glance accompanying poster, we provide an overview molecular mechanisms removal selective autophagy pathway, termed aggrephagy. We outline how aggrephagy regulated post-translational modifications via auxiliary proteins. further describe alternative pathways physiology disruption pathology. particular, discuss neurons wide range diseases. Finally, highlight strategies to reprogram treat aggregation

Language: Английский

---

Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes

Cell Reports, Journal Year: 2023, Volume and Issue: 42(5), P. 112448 - 112448

Published: May 1, 2023

Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), increasing phosphorylation of RAB GTPases through hyperactive kinase activity. We find that LRRK2-hyperphosphorylated RABs disrupt axonal transport autophagosomes by perturbing coordinated regulation cytoplasmic dynein and kinesin. In iPSC-derived human neurons, knockin strongly LRRK2-p.R1441H mutation causes striking impairments autophagosome transport, inducing frequent directional reversals pauses. Knockout opposing protein phosphatase 1H (PPM1H) phenocopies effect LRRK2. Overexpression ADP-ribosylation factor 6 (ARF6), a GTPase acts as switch for selective activation or kinesin, attenuates defects both p.R1441H PPM1H knockout neurons. Together, these findings support model where regulatory imbalance between ARF6 induces an unproductive "tug-of-war" disrupting processive transport. This disruption may contribute to PD pathogenesis impairing essential homeostatic functions autophagy.

Language: Английский

---

Dynein and dynactin move long-range but are delivered separately to the axon tip

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(5)

Published: Feb. 6, 2024

Axonal transport is essential for neuronal survival. This driven by microtubule motors including dynein, which transports cargo from the axon tip back to cell body. function requires its cofactor dynactin and regulators LIS1 NDEL1. Due difficulties imaging dynein at a single-molecule level, it unclear how this motor coordinate along length of axon. Here, we use neuron-inducible human stem line (NGN2-OPTi-OX) endogenously tag components visualize them near-single molecule regime. In retrograde direction, find that can move entire (>500 µm). Furthermore, NDEL1 also undergo long-distance movement, despite being mainly implicated with initiation transport. Intriguingly, in anterograde dynein/LIS1 moves faster than dynactin/NDEL1, consistent on different cargos. Therefore, neurons ensure efficient holding dynein/dynactin cargos over long distances but keeping separate until required.

Language: Английский

---

Extensive structural rearrangement of intraflagellar transport trains underpins bidirectional cargo transport

Cell, Journal Year: 2024, Volume and Issue: 187(17), P. 4621 - 4636.e18

Published: July 26, 2024

Bidirectional transport in cilia is carried out by polymers of the IFTA and IFTB protein complexes, called anterograde retrograde intraflagellar (IFT) trains. Anterograde trains deliver cargoes from cell to cilium tip, then convert into for cargo export. We set understand how IFT complexes can perform these two directly opposing roles before after conversion. use cryoelectron tomography situ cross-linking mass spectrometry determine structure compare it with known The train a 2-fold symmetric polymer organized around central thread complexes. conclude that anterograde-to-retrograde remodeling involves global rearrangements IFTA/B requires complete disassembly train. Finally, we describe conformational changes cargo-binding sites facilitate unidirectional bidirectional system.

Language: Английский

---

Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100053 - 100053

Published: March 1, 2025

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson Huntington amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due intricate pathogenesis substantial variability among patients, including differences in environmental exposures genetic predispositions. One of the defining characteristics NDs is widely reported be buildup misfolded proteins. For example, disease marked by amyloid beta hyperphosphorylated Tau aggregates, whereas exhibits α-synuclein aggregates. Amyotrophic sclerosis dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, fused-in sarcoma involves mutant huntingtin polyglutamine These proteins key biomarkers also serve potential therapeutic targets, they can addressed through autophagy, a process that removes excess cellular inclusions maintain homeostasis. Various forms macroautophagy, chaperone-mediated microautophagy, hold promise eliminating toxic implicated NDs. In this review, we focus on elucidating regulatory connections between autophagy NDs, summarizing cause exploring impact mechanisms, discussing how regulate aggregation. Moreover, underscore activation strategy across different small molecules capable activating pathways, rapamycin targeting mTOR pathway clear Sertraline AMPK/mTOR/RPS6KB1 Tau, further illustrate NDs' intervention. Together, these findings would provide new insights into current research trends propose small-molecule drugs promising strategies future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview eliminate aggregates neurodegenerative diseases. It elucidates fascinating interrelationships "chasing escaping" phenomenon. discusses progress utilizing activate improve efficacy therapies removing

Language: Английский

---