Extreme disorder in an ultrahigh-affinity protein complex

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.We thank D. L. Bajor (Vonderheide laboratory, University of Pennsylvania) for the gift of the R6560B cells. We thank L. Bojmar for carefully reviewing the paper. We thank S. Rudchenko and M. Barbu-Stevanovic at the Hospital for Special Surgery Fannie E. Rippel Foundation Flow Cytometry Core Facility for expert flow cytometry. We are supported by grants from the Children’s Cancer and Blood Foundation (H.P., D.L.), Manning Foundation (D.L.), Hartwell Foundation (D.L.), Champalimaud Foundation (D.L.), Fundacao para a Ciencia e a Tecnologia (D.L.), Nancy C and Daniel P Paduano Foundation (H.P., D.L.), Mary Kay Foundation (D.L.), Pediatric Oncology Experimental Therapeutic Investigator Consortium (D.L.), James Paduano Foundation (D.L., H.P.), Melanoma Research Alliance (H.P.), Sohn Conference Foundation (H.P.), Beth Tortolani Foundation (D.L., J.B.), Malcolm Hewitt Weiner Foundation (D.L.), Jose Carreras Leukemia Foundation (B.K.T.), Theodore Rapp Foundation (D.L.), American Hellenic Educational Progressive Association 5th District Cancer Research Foundation (D.L.), Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), Breast Cancer Alliance (J.B.), and Manhasset Women’s Coalition Against Breast Cancer (J.B.).S