Rare but Specific: 5-bp Composite Motifs Define SMAD Binding in BMP Signaling

Overview

Journal BMC Biol

Publisher Biomed Central

Specialty Biology

Date 2025 Mar 14

PMID 40082964

Authors

Jerome Jatzlau

Sophie-Nhi Do

Rebeca A Mees

Paul-Lennard Mendez

Rameez Jabeer Khan

Lukas Maas

Lidia Ruiz

Pau Martin-Malpartida

Maria J Macias

Petra Knaus

Affiliations

Soon will be listed here.

Abstract

Background: Receptor-activated SMADs trimerize with SMAD4 to regulate context-dependent target gene expression. However, the presence of a single SMAD1/5/8 binding motif in cis-regulatory elements alone does not trigger transcription in native contexts. We hypothesize that binding to composite motifs in which at least two SMAD binding sites are in close proximity would be enough to induce transcription as this scenario allows the simultaneous interaction of at least two SMAD proteins, thereby increasing specificity and affinity.

Results: Using more than 65 distinct firefly luciferase constructs, we delineated the minimal requirements for BMP-induced gene activation. We propose a model in which two SMAD-MH1 domains bind a SMAD-composite motif in a back-to-back fashion with a 5-bp distance between the SMAD-motifs on opposing DNA strands. However screening of SMAD1-bound regions across a variety of cell types highlights that these composite motifs are extremely uncommon, explaining below 1% of SMAD1 binding events.

Conclusions: Deviations from these minimal requirements prevent transcription and underline the need for co-transcription factors to achieve gene activation.

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