Mediator is a multiprotein co-activator of RNA polymerase (Pol) II transcription. Mediator contains a conserved core that comprises the 'head' and 'middle' modules. We present here a structure-function analysis of the essential Med11/22 heterodimer, a part of the head module. Med11/22 forms a conserved four-helix bundle domain with C-terminal extensions, which bind the central head subunit Med17. A highly conserved patch on the bundle surface is required for stable transcription pre-initiation complex formation on a Pol II promoter in vitro and in vivo and may recruit the general transcription factor TFIIH. The bundle domain fold is also present in the Mediator middle module subcomplex Med7/21 and is predicted in the Mediator heterodimers Med2/3, Med4/9, Med10/14 and Med28/30. The bundle domain thus represents a common building block that has been multiplied and functionally diversified during Mediator evolution in eukaryotes.
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http://dx.doi.org/10.1093/nar/gkr229 | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Neurotransmitter release is triggered in microseconds by Ca-binding to the Synaptotagmin-1 C-domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 CB domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca-binding loops away from the fusion site, hindering these putative activities.
View Article and Find Full Text PDFImplement Sci Commun
January 2025
Department of Obstetrics and Gynecology, Division of Maternal and Fetal Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
Background: Pregnancy related hypertension is a leading cause of preventable maternal morbidity and mortality in the US, with consistently higher rates affecting racial minorities. Many complications are preventable with timely treatment, in alignment with the Alliance for Innovation on Maternal Health's Patient Safety Bundle ("Bundle"). The Bundle has been implemented successfully in inpatient settings, but 30% of preeclampsia-related morbidity occurs in outpatient settings in North Carolina.
View Article and Find Full Text PDFChembiochem
January 2025
Nanjing University, School of Chemistry and Chemical Engineering, 163 Xianlin Avenue, 210023, Nanjing, CHINA.
DNA double crossover (DX) motifs including DAE (double crossover, antiparallel, even spacing) and DAO (double crossover, antiparallel, odd spacing) are well-known monolayered DNA building blocks for construction of 2D DNA arrays and tubes in nanoscale and microscale. Compared to the 3D architectures of DNA origami and single-stranded DNA bricks to build nanoscale 3D bundles, tessellations, gears, castles, etc., designs of double- and multi-layers of DX motifs for 3D architectures are still limited.
View Article and Find Full Text PDFAnticancer Agents Med Chem
January 2025
School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China.
The alternative splicing (AS) of pre-mRNA is an important process in controlling the expression of human genes, which can enrich the diversity of the proteome and regulate gene function. On the contrary, aberrant splicing contributes significantly to numerous human diseases progression, including tumors, neurological diseases, metabolic diseases, infections, and immune diseases. The PUF60, a protein related to RNA splicing, plays critical functions in RNA splicing and gene transcription regulation.
View Article and Find Full Text PDFAm J Obstet Gynecol MFM
January 2025
Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St Suite E8527, Baltimore, MD 21205; Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St Suite E8527, Baltimore, MD 21205; Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, 550 North Broadway Baltimore, MD 21205.
Background: Obstetric hemorrhage is the leading cause of maternal mortality and severe maternal morbidity (SMM) in Maryland and nationally. Currently, through a quality collaborative, the state is implementing the Alliance for Innovation on Maternal Health (AIM) patient safety bundle on obstetric hemorrhage.
Objective: To describe SMM events contributed by obstetric hemorrhage and their preventability in Maryland.
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