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Nuclear lamina strain states revealed by intermolecular force biosensor
In this work, a nanobody based intermolecular strain sensor was used to follow the mechanical strain in the nuclear lamina. The results indicate that mechanical state of the nuclear lamina is not only affected by the cell contractility, but also chromatin packing.
- Brooke E. Danielsson
- , Bobin George Abraham
- & Teemu O. Ihalainen
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| Open Access
Dynamic interplay between target search and recognition for a Type I CRISPR-Cas system
The details of CRISPR-Cas target search are unresolved. Here the authors analyse the target search process of the Type I CRISPR-Cas complex Cascade: they show that target search and target recognition are tightly linked, and DNA supercoiling and limited 1D diffusion play a role.
- Pierre Aldag
- , Marius Rutkauskas
- & Ralf Seidel
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Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat
Here, the authors develop a protein engineering method that enables high-resolution structural biology study of human fatty acid synthase. Using this technique, they uncover unique structural features of the enzyme and the mechanism of its inhibition by an anticancer drug Denifanstat.
- S. M. Naimul Hasan
- , Jennifer W. Lou
- & Mohammad T. Mazhab-Jafari
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Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42
AK-42 was reported as a specific inhibitor of ClC-2 but its working mechanism is not clear. Here authors report cryo-EM structures of apo ClC-2 and in complex with AK-42, revealing how it inhibits ClC-2 specifically.
- Tao Ma
- , Lei Wang
- & Huawei Zhang
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Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314
The authors highlight the importance of kinetics in GPCR activation. Using solution NMR, they show that the transducer βarrestin1 and the β-arrestin1biased ligand ML314 kinetically tune the conformational ensemble of the neurotensin receptor 1.
- Fabian Bumbak
- , James B. Bower
- & Joshua J. Ziarek
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Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering
Here the authors report time-resolved experiments showing that amyloid-β peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.
- Jaekyun Jeon
- , Wai-Ming Yau
- & Robert Tycko
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Symport and antiport mechanisms of human glutamate transporters
Ion gradients power the neurotransmitter transport by brain glutamate transporters. Here, the authors report cryo-EM structures of the EAAT3 transporter isoform with and without the ions and the neurotransmitter, revealing the coupling mechanisms.
- Biao Qiu
- & Olga Boudker
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Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site
LPL hydrolyzes triglycerides from lipoproteins. LPL can adopt many oligomeric forms. Here, the authors solve a 3.9 Å cryoEM structure of the previously uncharacterized LPL dimer. Key features include a C-terminal dimerization interface and a hydrophobic pore next to the active site.
- Kathryn H. Gunn
- & Saskia B. Neher
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Structural basis for the self-recognition of sDSCAM in Chelicerata
Combining structural, biochemical, and cellular evidence, the authors elucidate the self-recognition mechanism of a neuronal receptor sDSCAM and provide insights into the evolutionary landscape of the cell recognition molecule diversity.
- Jie Cheng
- , Yamei Yu
- & Qiang Chen
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Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Using a combination of MD simulations and NMR, the authors investigate how temperature affects allostery in imidazole glycerol phosphate synthase (IGPS), revealing that increase of temperature triggers local amino acid dynamics and providing insights into mechanism of allosteric regulation.
- Federica Maschietto
- , Uriel N. Morzan
- & Victor S. Batista
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Derepression may masquerade as activation in ligand-gated ion channels
Ligand-gated ion channels are activated/opened by agonists. Tessier et al. show that agonists can inhibit the inhibition of intrinsic basal activity, and thus that activation may instead be the manifestation of a derepression mechanism.
- Christian J. G. Tessier
- , Johnathon R. Emlaw
- & Corrie J. B. daCosta
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Molecular mechanism on forcible ejection of ATPase inhibitory factor 1 from mitochondrial ATP synthase
IF1 is a natural inhibitor of mitochondrial FoF1-ATP synthase, which blocks catalysis and rotation of the F1 motor. Here, the authors show the rotational-direction-dependence of activation from IF1 inhibition, with IF1 being readily dissociated when F1 rotates to the clockwise direction.
- Ryohei Kobayashi
- , Hiroshi Ueno
- & Hiroyuki Noji
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Inhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein–protein interaction
Protein phosphatase 1 (PP1) is regulated by intrinsically disordered proteins like inhibitor-3, I3. The authors show that I3 does not inhibit PP1 by forming a rigid complex but instead by binding dynamically with its active site metals, showing how flexibility is used in biology.
- Gautam Srivastava
- , Meng S. Choy
- & Wolfgang Peti
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Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders
eIF5A is the only protein known to contain hypusine. Here, the authors present the cryoEM structure of the eIF5A-DHS complex and provide mechanistic insights to understand the deoxyhypusination reaction and hypusination-related neurodegeneration.
- Elżbieta Wątor
- , Piotr Wilk
- & Przemysław Grudnik
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FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation
The authors used multi-disciplinary approaches to understand the structural mechanism underlying spontaneous aggregation of tau encoding an S320F FTD-tau mutant. Understanding the mechanisms of tau aggregation will help identify novel methods to regulate its misfolding.
- Dailu Chen
- , Sofia Bali
- & Lukasz A. Joachimiak
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Two gates mediate NMDA receptor activity and are under subunit-specific regulation
NMDA receptors are glutamate-gated ion channels that regulate fast signaling in the brain. Here, the authors show that the opening and closing patterns of the channel derive from the action of two gates that are regulated by distinct subunits.
- Johansen B. Amin
- , Miaomiao He
- & Lonnie P. Wollmuth
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Insights into receptor structure and dynamics at the surface of living cells
It is challenging to approach protein structures in living cells. Here the authors investigate Interleukin-4 receptor alpha, which has a noncanonical amino acid incorporated at different locations, and see that evaluating click efficiency with calibrated imaging gives information on structure-related properties.
- Frederik Steiert
- , Peter Schultz
- & Thomas Weidemann
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Robust automated backbone triple resonance NMR assignments of proteins using Bayesian-based simulated annealing
The authors present BARASA, an approach to assign backbone triple resonance spectra of proteins that augments traditional approaches with a Bayesian statistical analysis of the observed chemical shifts. The algorithm employs a simulated annealing engine to establish a consensus set of resonance assignments and is tested against systems ranging in size to over 450 amino acids including examples of intrinsically disordered proteins.
- Anthony C. Bishop
- , Glorisé Torres-Montalvo
- & A. Joshua Wand
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Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein
In this paper, the authors use hydrogen-deuterium exchange mass spectrometry to describe how the SARS-CoV-2 spike glycoprotein has evolved its structural dynamics features and receptor binding capability from the emergence of the original Wuhan isolate to the recent omicron variant. The findings reported shed light on the evolution of SARS-CoV-2 in the human population and the mechanisms of emergence of new variants.
- Valeria Calvaresi
- , Antoni G. Wrobel
- & Argyris Politis
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Molecular mechanism of biased signaling at the kappa opioid receptor
Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.
- Amal El Daibani
- , Joseph M. Paggi
- & Tao Che
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Structural basis of HIV-1 maturation inhibitor binding and activity
HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
- Sucharita Sarkar
- , Kaneil K. Zadrozny
- & Tatyana Polenova
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| Open Access
Robust total X-ray scattering workflow to study correlated motion of proteins in crystals
X-ray diffraction images contain a signal that is an untapped source of information on protein dynamics. Here, the authors lay out a general workflow for interpreting this diffuse scattering signal and expanding the capabilities of protein crystallography.
- Steve P. Meisburger
- , David A. Case
- & Nozomi Ando
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Ligand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor
Using hydrogen-deuterium exchange, the authors propose a model explaining how a classic transcription factor undergoes changes in its conformational ensemble in response to different ligands.
- Anum Glasgow
- , Helen T. Hobbs
- & Tanja Kortemme
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Structure of the planar cell polarity cadherins Fat4 and Dachsous1
Fat and Dachsous are large cadherins that regulate planar polarity as a receptor:ligand pair. Here, authors determine the structure of the Fat:Dachsous complex to uncover the molecular determinants of binding and posttranslational modification.
- Elliot Medina
- , Yathreb Easa
- & Vincent C. Luca
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Structural basis of the mycobacterial stress-response RNA polymerase auto-inhibition via oligomerization
Biological processes can be regulated via oligomerization of macromolecules into high-order symmetric structures. Here, authors reported high-order structure of RNA polymerase and its role in regulation of gene expression in pathogenic bacterium.
- Zakia Morichaud
- , Stefano Trapani
- & Konstantin Brodolin
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Metamorphism in TDP-43 prion-like domain determines chaperone recognition
In this work, the authors show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease and stress the relevance of post-translationally modified chains as the targets for disease intervention.
- Jaime Carrasco
- , Rosa Antón
- & Javier Oroz
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| Open Access
Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition
RNA molecules aggregate in certain conditions, but how and why remains unclear. Here the authors develop a model that quantitatively explains the conditions and mechanism of RNA aggregation, and predicts a surprising non-monotonicity in the transition.
- Ofer Kimchi
- , Ella M. King
- & Michael P. Brenner
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Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus
The PIK3CA gene is one of the most frequently mutated genes in all of human cancer. Here authors describe the molecular mechanisms underlying how different oncogenic mutations in PIK3CA mediate increased activity.
- Meredith L. Jenkins
- , Harish Ranga-Prasad
- & John E. Burke
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Structure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs
A subset of Sec14 domain proteins use their gated hydrophobic pocket to bind and transport lipids. Here the authors provide structural and biochemical data revealing how the Sec14-fold of a Rho-GEF forms a surface groove that interacts with lysolipids.
- Yunfeng Li
- , Yulia Pustovalova
- & Bing Hao
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Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells
Aromatic amino acids in proteins support ligand binding and protein stability. To parse the physiocochemical roles of aromatic interactions, here Galles, Infield and co-authors identify pyrrolysine-based aminoacyl-tRNA synthetases that enable the encoding of fluorinated phenylalanine amino acids.
- Grace D. Galles
- , Daniel T. Infield
- & Christopher A. Ahern
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Morphological control enables nanometer-scale dissection of cell-cell signaling complexes
Micropatterning on electron microscopy grids enables control of cell positioning and arrangement. Here, the authors describe detailed nanoscale characterization of a micropatterning workflow for reproducible molecular characterization through cryo-ET
- Liam P. Dow
- , Guido Gaietta
- & Dorit Hanein
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A unifying Bayesian framework for merging X-ray diffraction data
Observation of the chemical and conformational dynamics of biomolecules by diffraction methods is impeded by several physical artifacts. The authors present an extensible framework for accurate correction of such data that can keep pace with rapid developments in diffraction methods.
- Kevin M. Dalton
- , Jack B. Greisman
- & Doeke R. Hekstra
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| Open Access
The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.
- Alessandra Dall’Agnese
- , Jesse M. Platt
- & Richard A. Young
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Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins
Arginine-rich proteins display reentrant LLPS behavior with changes in salt and temperature due to the hydrophobicity of arginine. Controlling the reentrant LLPS behavior opens avenues for the bioengineering and drug delivery fields.
- Yuri Hong
- , Saeed Najafi
- & Dong Soo Hwang
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Predicting protein function and orientation on a gold nanoparticle surface using a residue-based affinity scale
The orientation of proteins on nanoparticle surfaces is important to the nanoparticle’s fate in vivo. Here, the authors use competitive binding between protein variants to develop a residue-based affinity scale to develop a model for the binding and orientation of proteins on gold nanoparticles
- Joanna Xiuzhu Xu
- , Md. Siddik Alom
- & Nicholas C. Fitzkee
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Structure- and computational-aided engineering of an oxidase to produce isoeugenol from a lignin-derived compound
Lignin can be depolymerized into 4-alkylphenols by chemical means. Here the authors show a three-step computational-assisted enzyme engineering process to generate a biocatalyst for the conversion of lignin-derived 4-n-propylguaiacol into isoeugenol, a valuable compound.
- Yiming Guo
- , Laura Alvigini
- & Marco W. Fraaije
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| Open Access
Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity
It is known that the T cell co-receptor CD4 greatly enhances the capacity of T cell receptor (TCR) signalling, triggered by the peptide-bound MHC molecule. Here authors show that the mechanistic basis for the enhancement is the co-operative binding of TCR and CD4 to the MHC-peptide complex.
- Muaz Nik Rushdi
- , Victor Pan
- & Cheng Zhu
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F-actin architecture determines constraints on myosin thick filament motion
While the impact of F-actin architecture on stress transmission is well studied, the role of architecture on stress generation remains unclear. Here authors use in vitro model and show that distinct organizations constrain myosin motion.
- Camelia G. Muresan
- , Zachary Gao Sun
- & Michael P. Murrell
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Optical cavity-mediated exciton dynamics in photosynthetic light harvesting 2 complexes
Light-matter interaction can induce changes to the properties of the system by creating hybrid collective states of light and molecular excitations, the so called polaritons. Here the authors use femtosecond pump-probe spectroscopy to explore exciton-polariton dynamics in a photosynthetic protein, light harvesting 2 complexes, and find evidence for rapid energy transfer to dark polariton states.
- Fan Wu
- , Daniel Finkelstein-Shapiro
- & Tönu Pullerits
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Magic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation
In this work the authors report the structure of nucleotide-free kinesin-1 motor domain (apo-KIF5B) in complex with paclitaxel-stabilized microtubules using magic-angle-spinning (MAS) NMR spectroscopy. The study provides insights into the dynamic changes under which the neck linker goes upon binding to ADP.
- Chunting Zhang
- , Changmiao Guo
- & Tatyana Polenova
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| Open Access
Programmable self-regulated molecular buffers for precise sustained drug delivery
Natural buffer molecules ensure the controlled and precise delivery of specific molecules in biology. Here, the authors replicate the natural buffer systems using aptamers with controlled binding efficiency to control and maintain the levels of free drugs both in vitro and in vivo.
- Arnaud Desrosiers
- , Rabeb Mouna Derbali
- & Alexis Vallée-Bélisle
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| Open Access
Binary-FRET reveals transient excited-state structure associated with activity-dependent CaMKII - NR2B binding and adaptation
FRET can be used to study conformational changes and protein-protein interactions. Here the authors report Binary-FRET for monitoring two FRET reactions, one encoded in the fluorescence lifetime of the donor, another encoded in its anisotropy, and monitor the dynamics of CaMKII and its interaction with NR2B.
- Tuan A. Nguyen
- , Henry L. Puhl III
- & Steven S. Vogel
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| Open Access
Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor
Meprin α is a proteolytic regulator of the extracellular matrix that forms enormous oligomeric filaments of unknown purpose. Here, the authors determine by cryo-EM the structural basis of the meprin supercoiled filament and further characterise a small molecule inhibitor bound to its active site.
- Charles Bayly-Jones
- , Christopher J. Lupton
- & James C. Whisstock
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| Open Access
A simple thermodynamic description of phase separation of Nup98 FG domains
The nuclear pore complex (NPC) barrier is a selective phase assembled from disordered but cohesive FG domains. The authors provide a thermodynamic description of an FG phase that is ultimately simplified and yet closely recapitulates NPC transport selectivity.
- Sheung Chun Ng
- & Dirk Görlich
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| Open Access
Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis
Amyloid fibrils of β2-microglobulin (β2m) can cause dialysis-related amyloidosis. Here, the authors show that a decrease in serum albumin levels in long-term dialysis deteriorates the inhibitory effects of serum milieux on supersaturation-limited amyloid formation of β2m, suggesting that macromolecular crowding protects the onset of amyloidosis.
- Kichitaro Nakajima
- , Keiichi Yamaguchi
- & Yuji Goto
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| Open Access
FtsN maintains active septal cell wall synthesis by forming a processive complex with the septum-specific peptidoglycan synthases in E. coli
FtsN promotes the inward synthesis of septal peptidoglycan (sPG) through the FtsWI complex during bacterial cell division. Here, Lyu et al. apply single-molecule microscopy on E. coli to show that FtsN proteins (I) move processively at a speed similar to that of FtsWI molecules. (II) can be divided into two populations based on their speeds, and (III) their movement is driven exclusively by peptidoglycan synthesis
- Zhixin Lyu
- , Atsushi Yahashiri
- & Jie Xiao
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| Open Access
The evolutionary advantage of an aromatic clamp in plant family 3 glycoside exo-hydrolases
Barley β-d-glucan glucohydrolase is a glycoside hydrolase family 3 (GH3) enzyme critical for growth and development. Here the authors carryout mutagenesis, structural analyses and multi-scale molecular dynamics to examine the binding and conformational behaviour of several β-d-glucosides during the substrate-product assisted catalysis that operates in GH3 hydrolases.
- Sukanya Luang
- , Xavier Fernández-Luengo
- & Maria Hrmova
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| Open Access
Cytoplasmic organization promotes protein diffusion in Xenopus extracts
Cytoplasmic organization is a hallmark of living cells. Here, the authors make use of self-organizing cell extracts to examine how the emergence of large-scale organizations influences the microscopic diffusion of protein molecules in the cytoplasm.
- William Y. C. Huang
- , Xianrui Cheng
- & James E. Ferrell Jr
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| Open Access
QuasAr Odyssey: the origin of fluorescence and its voltage sensitivity in microbial rhodopsins
The authors present an in-depth investigation of excited state dynamics and molecular mechanism of the voltage sensing in microbial rhodopsins. Using a combination of spectroscopic investigations and molecular dynamics simulations, the study proposes the voltage-modulated deprotonation of the chromophore as the key event in the voltage sensing. Thus, molecular constraints that may further improve the fluorescence quantum yield and the voltage sensitivity are presented.
- Arita Silapetere
- , Songhwan Hwang
- & Peter Hegemann
Cryo-EM and femtosecond spectroscopic studies provide mechanistic insight into the energy transfer in CpcL-phycobilisomes