Structural insights into a highly flexible zinc finger module unravel INSM1 function in transcription regulation

Structural insights into a highly flexible zinc finger module unravel INSM1 function in transcription regulation

Blog Article

Abstract Orderly development of neuroendocrine and nervous system of mammals requires INSM1, a key regulator for cell differentiation.Ectopic expression of INSM1 is closely correlated with human neuroendocrine tumorigenesis, which makes INSM1 a reliable diagnostic biomarker and potential therapeutic target.To date, INSM1 is known as a transcription repressor binding to GGGG-contained DNA element and TEAD1 using its five zinc fingers (ZFs), while the binding mechanism remains unknown.Here, we reveal highly variable conformations of the whole structure of the five urethral-sounds ZFs, among which ZF1 adopts an unusual CCHC-fold.ZF1 binds to the TEAD domain of TEAD1 through hydrophobic interactions, and forms a ternary complex with TEAD1 and console cover top TEAD1-targeted DNA.

Based on this, INSM1 cooperates with TEAD1 to repress the transcription of TEAD1-targeted genes.ZF2 and ZF3 of INSM1 can bind to DNA but have no specificity to the GGGG-contained element due to long flexible interdomain linker.Instead, INSM1 collaborates with CTCF to target genome loci having the GGGG-contained element and regulate the expression of adjacent genes.This study defines a functional mode of INSM1 by cooperating with diverse DNA-binding proteins for targeting specific genome loci in transcription regulation, and provides structural information for designing INSM1-related therapeutic drugs and diagnostic probes.