The PAX3 paired domain and homeodomain function as a single binding module in vivo to regulate subnuclear localization and mobility by a mechanism that requires base-specific recognition

Journal of Molecular Biology
Gareth N CorryD Alan Underhill

Abstract

The transcription factor PAX3 is essential for myogenesis and neural crest development, and is one of several genes mutated in human Waardenburg syndrome. Analysis of disease-causing missense mutations in PAX3 has established the interdependence of its two DNA-binding domains, the paired domain (PD) and the homeodomain (HD), as well as defects in localization and mobility. Paradoxically, mutants that retained DNA binding activity exhibited the greatest defects in localization and mobility, regardless of the domain in which they reside. In the present study, structure-function analyses were used to determine the mechanistic basis of this effect. In the context of the isolated DNA-binding domains, HD mutants adopted an increase in mobility proportional to their loss in DNA binding, while PD mutants continued to display the inverse relationship observed in the full-length protein. At the structural level, this reflected an unexpected dependence on base-specific contacts in the PD, whereas HD mobility was more severely affected by loss of backbone contacts, as has been observed with other DNA-binding proteins. This requires that the HD switch to a base-specific mode in the full-length protein. Moreover, both domains underwent subst...Continue Reading

References

Mar 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·P H von Hippel, O G Berg
Apr 25, 1995·Proceedings of the National Academy of Sciences of the United States of America·D A UnderhillP Gros
Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·J A EpsteinR L Maas
May 28, 1996·Proceedings of the National Academy of Sciences of the United States of America·J L BennicelliF G Barr
May 30, 1997·The Journal of Biological Chemistry·D A Underhill, P Gros
Aug 1, 1997·Journal of Medical Genetics·A P Read, V E Newton
Mar 21, 1998·Nature Genetics·A WatanabeM Tachibana
Sep 10, 1999·The Journal of Biological Chemistry·M D GalibertC R Goding
Oct 16, 1999·Gene·T D BarberT B Friedman
Oct 18, 2000·The Journal of Clinical Investigation·D LangJ A Epstein
Dec 5, 2000·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·D A Underhill
Aug 3, 2001·Nature·S J NielsenT Kouzarides
Dec 26, 2001·Trends in Genetics : TIG·Neil Chi, Jonathan A Epstein
Mar 4, 2003·Molecular and Cellular Biology·Marcel J M Schaaf, John A Cidlowski
Apr 2, 2003·Human Molecular Genetics·Deborah Lang, Jonathan A Epstein
Apr 28, 2004·Journal of Structural Biology·Pascal FarlaAdriaan B Houtsmuller
Jun 24, 2004·Journal of Cellular Biochemistry·Z Dave SharpMichael A Mancini
Jul 9, 2004·Genome Biology·Luis A ParadaTom Misteli
Oct 7, 2004·Biophysical Journal·Michael Slutsky, Leonid A Mirny
Nov 4, 2004·Bulletin of Mathematical Biology·G CarreroG de Vries

❮ Previous
Next ❯

Citations

Sep 18, 2012·Nature Structural & Molecular Biology·Aydan Bulut-KarsliogluThomas Jenuwein
Nov 26, 2011·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Siu Wah Wong-DeyrupSonya J Franklin
Oct 20, 2012·Stem Cells·Alessandro MagliRita C R Perlingeiro
Feb 26, 2013·Expert Opinion on Therapeutic Targets·Mary E Olanich, Frederic G Barr
Sep 17, 2013·Developmental Biology·Charis L HimedaCharles P Emerson
Sep 30, 2020·American Journal of Medical Genetics. Part a·Puneeth H SomashekarAnju Shukla
Jun 22, 2018·Scientific Reports·Thomas B Barton-OwenIldikó M L Somorjai

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.