Collagen's enigmatic, highly conserved -glycan has an essential proteostatic function.

Intracellular procollagen folding begins at the protein's C-terminal propeptide (C-Pro) domain, which initiates triple-helix assembly and defines the composition and chain register of fibrillar collagen trimers. The C-Pro domain is later proteolytically cleaved and excreted from the body, while the mature triple helix is incorporated into the extracellular matrix. The procollagen C-Pro domain possesses a single -glycosylation site that is widely conserved in all the fibrillar procollagens across humans and diverse other species.

Elucidation of proteostasis defects caused by osteogenesis imperfecta mutations in the collagen-α2(I) C-propeptide domain.

Intracellular collagen assembly begins with the oxidative folding of ∼30-kDa C-terminal propeptide (C-Pro) domains. Folded C-Pro domains then template the formation of triple helices between appropriate partner strands. Numerous C-Pro missense variants that disrupt or delay triple-helix formation are known to cause disease, but our understanding of the specific proteostasis defects introduced by these variants remains immature.

A cysteine-based molecular code informs collagen C-propeptide assembly.

Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen's C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization.

Phage Display of Dynamic Covalent Binding Motifs Enables Facile Development of Targeted Antibiotics.

Antibiotic resistance of bacterial pathogens poses an increasing threat to the wellbeing of our society and urgently calls for new strategies for infection diagnosis and antibiotic discovery. The antibiotic resistance problem at least partially arises from extensive use of broad-spectrum antibiotics. Ideally, for the treatment of infection, one would like to use a narrow-spectrum antibiotic that specifically targets and kills the disease-causing strain.

Non-additive stabilization by halogenated amino acids reveals protein plasticity on a sub-angstrom scale.

It has been a long-standing goal to understand the structure-stability relationship of proteins, as optimal stability is essential for protein function and highly desirable for protein therapeutics. Halogenation has emerged as a minimally invasive strategy to probe the physical characteristics of proteins in solution, as well as enhance the structural stabilities of proteins for therapeutic applications. Although advances in synthetic chemistry and genetic code expansion have allowed for the rapid synthesis of proteins with diverse chemical sequences, much remains to be learned regarding the impact of these mutations on their structural integrity.

Metal-Assisted Folding of Prolinomycin Allows Facile Design of Functional Peptides.

Cyclic peptides have been proposed as privileged scaffolds that might mimic the folding and function of natural proteins. However, simple cyclic peptides typically cannot fold into well-defined structures. Herein, we describe a foldable cyclic peptide scaffold on which functional side chains can be displayed for targeted recognition of biomolecules.

6-Azabicyclo[3.2.1]octanes Via Copper-Catalyzed Enantioselective Alkene Carboamination.

Bridged bicyclic rings containing nitrogen heterocycles are important motifs in bioactive small organic molecules. An enantioselective copper-catalyzed alkene carboamination reaction that creates bridged heterocycles is reported herein. Two new rings are formed in this alkene carboamination reaction where -sulfonyl-2-aryl-4-pentenamines are converted to 6-azabicyclo[3.

Understanding Lipid Recognition by Protein-Mimicking Cyclic Peptides.

This paper describes our investigation of the structural determinants of a designed cyclic peptide (cLac, cyclic peptide mimicking lactadherin) for phosphatidylserine (PS) recognition. A highly efficient strategy that takes advantage of the native chemical ligation (NCL) chemistry has been developed for the synthesis and labeling of cyclic peptides in general. Ala scanning of the cLac peptide revealed a sophisticated model for PS binding, in which the peptide scaffold assembles multiple polar residues to balance the desolvation and electrostatic interactions (salt bridge and hydrogen bonding) to achieve lipid selectivity.

Copper-catalyzed intramolecular alkene carboetherification: synthesis of fused-ring and bridged-ring tetrahydrofurans.

Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C-H functionalization provides the C-C bond.