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1.
Commun Biol ; 6(1): 1158, 2023 11 13.
Article in English | MEDLINE | ID: mdl-37957226

ABSTRACT

Cryptophyte algae have a unique phycobiliprotein light-harvesting antenna that fills a spectral gap in chlorophyll absorption from photosystems. However, it is unclear how the antenna transfers energy efficiently to these photosystems. We show that the cryptophyte Hemiselmis andersenii expresses an energetically complex antenna comprising three distinct spectrotypes of phycobiliprotein, each composed of two αß protomers but with different quaternary structures arising from a diverse α subunit family. We report crystal structures of the major phycobiliprotein from each spectrotype. Two-thirds of the antenna consists of open quaternary form phycobiliproteins acting as primary photon acceptors. These are supplemented by a newly discovered open-braced form (~15%), where an insertion in the α subunit produces ~10 nm absorbance red-shift. The final components (~15%) are closed forms with a long wavelength spectral feature due to substitution of a single chromophore. This chromophore is present on only one ß subunit where asymmetry is dictated by the corresponding α subunit. This chromophore creates spectral overlap with chlorophyll, thus bridging the energetic gap between the phycobiliprotein antenna and the photosystems. We propose that the macromolecular organization of the cryptophyte antenna consists of bulk open and open-braced forms that transfer excitations to photosystems via this bridging closed form phycobiliprotein.


Subject(s)
Cryptophyta , Photosynthesis , Phycobiliproteins/chemistry , Phycobiliproteins/metabolism , Chlorophyll
2.
Redox Biol ; 38: 101790, 2021 01.
Article in English | MEDLINE | ID: mdl-33202300

ABSTRACT

Superoxide dismutase (SOD) is known to be protective against oxidative stress-mediated skin dysfunction. Here we explore the potential therapeutic activities of RM191A, a novel SOD mimetic, on skin. RM191A is a water-soluble dimeric copper (Cu2+-Cu3+)-centred polyglycine coordination complex. It displays 10-fold higher superoxide quenching activity compared to SOD as well as significant antioxidant, anti-inflammatory and immunomodulatory activities through beneficial modulation of several significant inflammatory cytokines in vitro and in vivo. We tested the therapeutic potential of RM191A in a topical gel using a human skin explant model and observed that it significantly inhibits UV-induced DNA damage in the epidermis and dermis, including cyclobutane pyrimidine dimers (CPD), 8-oxo-guanine (8-oxoG) and 8-nitroguanine (8NGO). RM191A topical gel is found to be non-toxic, non-teratogenic and readily distributed in the body of mice. Moreover, it significantly accelerates excisional wound healing, reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation and attenuates age-associated oxidative stress in skin, demonstrating both skin regenerative and geroprotective properties of RM191A.


Subject(s)
Skin Neoplasms , Skin , Animals , Epidermis , Mice , Superoxide Dismutase , Tetradecanoylphorbol Acetate
3.
J Med Chem ; 63(5): 2181-2193, 2020 03 12.
Article in English | MEDLINE | ID: mdl-31347843

ABSTRACT

Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70%; however, children are often left with long-term treatment side effects. New therapies that maintain a high cure rate while reducing off-target toxicity are required. We describe for the first time the use of a bacteriophage-peptide display library to identify heptapeptides that bind to medulloblastoma cells. Two heptapeptides that demonstrated high [E1-3 (1)] or low [E1-7 (2)] medulloblastoma cell binding affinity were synthesized. The potential of the peptides to deliver a therapeutic drug to medulloblastoma cells with specificity was investigated by conjugating E1-3 (1) or E1-7 (2) to doxorubicin (5). Both peptide-drug conjugates were cytotoxic to medulloblastoma cells. E1-3 doxorubicin (3) could permeabilize an in vitro blood-brain barrier and showed a marked reduction in cytotoxicity compared to free doxorubicin (5) in nontumor cells. This study provides proof-of-concept for developing peptide-drug conjugates to inhibit medulloblastoma cell growth while minimizing off-target toxicity.


Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , Doxorubicin/administration & dosage , Drug Carriers/metabolism , Medulloblastoma/drug therapy , Oligopeptides/metabolism , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain Neoplasms/metabolism , Cell Line , Cell Line, Tumor , Child , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Drug Carriers/chemistry , Drug Delivery Systems , Humans , Medulloblastoma/metabolism , Oligopeptides/chemistry , Peptide Library
4.
Angew Chem Int Ed Engl ; 56(29): 8384-8388, 2017 07 10.
Article in English | MEDLINE | ID: mdl-28128487

ABSTRACT

The fold of a protein is encoded by its amino acid sequence, but how complex multimeric proteins fold and assemble into functional quaternary structures remains unclear. Here we show that two structurally different phycobiliproteins refold and reassemble in a cooperative manner from their unfolded polypeptide subunits, without biological chaperones. Refolding was confirmed by ultrafast broadband transient absorption and two-dimensional electronic spectroscopy to probe internal chromophores as a marker of quaternary structure. Our results demonstrate a cooperative, self-chaperone refolding mechanism, whereby the ß-subunits independently refold, thereby templating the folding of the α-subunits, which then chaperone the assembly of the native complex, quantitatively returning all coherences. Our results indicate that subunit self-chaperoning is a robust mechanism for heteromeric protein folding and assembly that could also be applied in self-assembled synthetic hierarchical systems.


Subject(s)
Light-Harvesting Protein Complexes/chemistry , Molecular Chaperones/chemistry , Hydrogen-Ion Concentration , Models, Molecular , Protein Refolding
5.
Angew Chem Int Ed Engl ; 54(18): 5317-22, 2015 Apr 27.
Article in English | MEDLINE | ID: mdl-25736460

ABSTRACT

Polymersomes provide a good platform for targeted drug delivery and the creation of complex (bio)catalytically active systems for research in synthetic biology. To realize these applications requires both spatial control over the encapsulation components in these polymersomes and a means to report where the components are in the polymersomes. To address these twin challenges, we synthesized the protein-polymer bioconjugate PNIPAM-b-amilFP497 composed of thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) and a green-fluorescent protein variant (amilFP497). Above 37 °C, this bioconjugate forms polymersomes that can (co-)encapsulate the fluorescent drug doxorubicin and the fluorescent light-harvesting protein phycoerythrin 545 (PE545). Using fluorescence lifetime imaging microscopy and Förster resonance energy transfer (FLIM-FRET), we can distinguish the co-encapsulated PE545 protein inside the polymersome membrane while doxorubicin is found both in the polymersome core and membrane.


Subject(s)
Acrylic Resins/chemistry , Acrylic Resins/chemical synthesis , Drug Carriers/chemical synthesis , Green Fluorescent Proteins/chemistry , Luminescent Proteins/chemical synthesis , Phycoerythrin/chemistry , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Drug Compounding , Fluorescence Resonance Energy Transfer , Hydrophobic and Hydrophilic Interactions , Luminescent Proteins/chemistry , Microscopy, Confocal , Microscopy, Fluorescence , Particle Size , Phase Transition , Surface Properties , Temperature
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