SUMMARY
Despite the essential functions of Hsp90, little is known about the
mechanism that controls substrate entry into its chaperone cycle. We show that
the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find
that it participates in the selective recruitment of only client kinases. Cdc37
recognizes kinase specificity determinants in both clients and nonclients and
acts as a general kinase scanning factor. Kinase sorting within the
client-to-nonclient continuum relies on the ability of Cdc37 to challenge the
conformational stability of clients by locally unfolding them. This metastable
conformational state has high affinity for Cdc37 and forms stable complexes
through a multidomain cochaperone interface. The interaction with nonclients is
not accompanied by conformational changes of the substrate and results in
substrate dissociation. Collectively, Cdc37 performs a quality control of
protein kinases, where induced conformational instability acts as a
“flag” for Hsp90 dependence and stable cochaperone
association.
Summary
The anti‐tumor immune response is considered to be due to the T‐cell receptor (TCR) binding to tumor antigens, which can be either wild‐type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity‐determining region‐3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3‐mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high‐priority neo‐antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor‐infiltrating lymphocytes.
Background
Pediatric cancer survival rates overall have been improving, but neuroblastoma (NBL) and acute lymphoblastic leukemia (ALL), two of the more prevalent pediatric cancers, remain particularly challenging. One issue not yet fully addressed is distinctions attributable to age of diagnosis.
Methods
In this report, we verified a survival difference based on diagnostic age for both pediatric NBL and pediatric ALL datasets, with younger patients surviving longer for both diseases. We identified several gene expression markers that correlated with age, along a continuum, and then used a series of age-independent survival metrics to filter these initial correlations.
Results
For pediatric NBL, we identified 2 genes that are expressed at a higher level in lower surviving patients with an older diagnostic age; and 4 genes that are expressed at a higher level in longer surviving patients with a younger diagnostic age. For pediatric ALL, we identified 3 genes expressed at a higher level in lower surviving patients with an older diagnostic age; and 17 genes expressed at a higher level in longer surviving patients with a younger diagnostic age.
Conclusions
This process implicated pan-chromosome effects for chromosomes 11 and 17 in NBL; and for the X chromosome in ALL.
Electronic supplementary material
The online version of this article (10.1186/s12935-019-0790-5) contains supplementary material, which is available to authorized users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.