@article{toledo_ica512_2019,
	title = {{ICA}512 {RESP}18 homology domain is a protein condensing factor and insulin fibrillation inhibitor},
	rights = {© 2019, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-{NonCommercial}-{NoDerivs} 4.0 International), {CC} {BY}-{NC}-{ND} 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/},
	url = {https://www.biorxiv.org/content/10.1101/521351v2},
	doi = {10.1101/521351},
	abstract = {{\textless}p{\textgreater}Type 1 diabetes islet cell autoantigen 512 ({ICA}512) is a tyrosine phosphatase-like intrinsic membrane protein involved in the biogenesis and turnover of insulin secretory granules ({SGs}) in pancreatic islet β-cells. Whereas its membrane proximal and cytoplasmic domains have been functionally and structurally characterized, the role of {ICA}512 N-terminal segment named regulated endocrine-specific protein 18 homology domain ({RESP}18HD), which encompasses residues 35-131, remains largely unknown. Here we show that {ICA}512 {RESP}18HD residues 91-131 encode for an intrinsically disordered region ({IDR}), which in vitro acts as a condensing factor for the reversible aggregation of insulin and other β-cell proteins in a {pH} and Zn2+ regulated fashion. At variance with what has been shown for other granule cargoes with aggregating properties, the condensing activity of {ICA}512 {RESP}18HD is displayed at {pH} close to neutral, i.e. in the {pH} range found in the early secretory pathway, while it is resolved at acidic {pH} and Zn2+ concentrations resembling those present in mature {SGs}. Moreover, we show that {ICA}512 {RESP}18HD residues 35-90, preceding the {IDR}, inhibit insulin fibrillation in vitro. Finally, we found that glucose-stimulated secretion of {RESP}18HD upon exocytosis of {SGs} from insulinoma {INS}-1 cells is associated with cleavage of its {IDR}, conceivably to prevent its aggregation upon exposure to neutral {pH} in the extracellular milieu. Taken together, these findings point to {ICA}512 {RESP}18HD being a condensing factor for protein sorting and granulogenesis early in the secretory pathway, and for prevention of amyloidogenesis.{\textless}/p{\textgreater}},
	pages = {521351},
	journaltitle = {{bioRxiv}},
	author = {Toledo, Pamela L. and Torkko, Juha M. and Müller, Andreas and Wegbrod, Carolin and Sönmez, Anke and Solimena, Michele and Ermácora, Mario R.},
	urldate = {2019-03-07},
	date = {2019-01-21},
	langid = {english},
	keywords = {{WP}5},
}