Zhou, Yadi | Search NASA

DOE OSTI2021

Extensins: Self-Assembly, Crosslinking, and the Role of Peroxidases

The extensin (EXT) network is elaborated by the covalent intermolecular crosslinking of EXT glycoprotein monomers, and its proper assembly is important for numerous aspects of basic wall architecture and cellular defense. In this review, we discuss new advances in the secretion of EXT monomers and the molecular drivers of EXT network self-assembly. Many of the functions of EXTs are conferred through covalent crosslinking into the wall, so we also discuss the different types of known intermolecular crosslinks, the enzymes that are involved, as well as the potential for additional crosslinks that are yet to be identified. EXTs also function in wall architecture independent of crosslinking status, and therefore, we explore the role of non-crosslinking EXTs. As EXT crosslinking is upregulated in response to wounding and pathogen infection, we discuss a potential regulatory mechanism to control covalent crosslinking and its relationship to the subcellular localization of the crosslinking enzymes.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2021

Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. Further, we experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.

59 BASIC BIOLOGICAL SCIENCES↗