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The SRY protein is a 223 residues long monomeric polypeptide ^[1]. It is a transcriptionnal factor, It activates the Müllerian Inhibiting Substance (MIS gene). It is encoded by the testis-determining sex gene and is itself involved in the sex determination in mammels by being responsible for the male sexual developement.

History

After centuries of unfounded theories mainly based on environmental factors, the first molecular theory concerning the sex determination appeared in 1891. At this time, the german biologist Hermann Henking was studying sperm formation in wasps. As a chromosome which was not present in all the wasps looked different from the others, he suspected it to play a role in sex determination and called it the "X chromosome". Ten years later, Clarence Erwin McClung saw that this chromosome behaved differently during the meiosis and was only present in half the sperm cells of grasshoppers. As the main characteristic that varies in 50/50 proportions among zygotes is the sex, McClung suspected the X chromosome to be implicated in sexual development. In 1905, Nettie Stevens discovered the "Y chromosome" (and the female XX and male XY patterns) while she was counting the chromosomes of beetles under the microscope^[2]. During the next decades, a few theories were in competition. In 1921, Calvin Bridges's works on Drosophila melanogaster seemed to reveal that male characters acquisition is due to a genic balance between the genes contained in the X chromosome and those contained in the autosomes^[3]. In 1930, Ronald Fisher introduced the first Y-based control of sex theory by proposing two different models : either all the genes responsible for the male characters are located on the Y chromosome or there is a Y-located gene which regulates the expression of genes elsewhere in the genome^[4]. As Alfred Jost had shown the testosterone produced by the testis is responsible for the entire male phenotype acquisition^[5], in 1988, Peter Neville Goodfellow proposed that there is a gene (TDF in human, Tdy in mice) on the Y chromosome which drives the development of the testis.^[6] In 1990, Goodfellow's hypothesis was validated with the discovery of Tdy's localisation. This gene's product (expressed during the male gonadal development) owns an amino-acid motif showing homology to other known or putative DNA-binding domains. Tdy is therefore a transcriptional factor^[7]. The same year, the human SRY gene (accepted later as the TDF) was discovered^[8]. Three dimensional structure of the SRY protein was determined in 1995 using NMR spectroscopy^[9]

SRY gene

The SRY gene encodes the SRY protein. It is located on the Y chromosom.

Structure

The SRY-HMG domain (HMG-Box)

SRY-HMG stands for Sex determining Region Y - High Mobility Group domain. It is approximately 80 residues long. It mediates the binding of the protein to the minor groove of DNA. It has a Twisted L shape meaning that it has a long (28Å) and a short (22Å) arm. The HMG Box is made of 3 helices, its N-term and C-term are irregular. ^[10]. the overall Structure is stabilized by a hydrophobic core.

The interaction between the HMG-Box and DNA is specific and stable. It permits the bend of DNA (≈75°). It is mostly hydrophobic interaction. Only one molecule of water interface the Box and the DNA. the complex is stabilized by salt bridges between positive charged residues of the HMG domain and negative charged phosphates.^[11]

Even if the most important function of the HMG box is its capacity of binding DNA, it is also involved in:

• DNA bending
• DNA condensation
• Recombination
• Transcription activation
• DNA repair

There are 2 kinds of protein that contain a HMG box

• HMG1 : It is expressed in few cell types. It is found in transcription factors that contain a single HMG box. The bind to a DNA sequence is specific.
• HMG2 : Are found in all cell types and are abundant in chromatin. This proteins can contain two or more HMG boxes that can nonspecifically bind DNA.

General structure of SRY

3 domains:

• N-term domain
• Central domain : DNA binding (HMG box)
• C-term domain

Structure of the DNA target site

The DNA target site is a DNA octamer : d(GCACAAAC).

Function

Sex determining

It acts like a sex determinator thanks to it transcriptionnal activity. It inhibits the developpement of female sex structure in th embryonnic individual.

Implication - Future for SRY ?

Disease

It has been shown that a mutation of SRY increase male to female sex reversal for 15% REF NECESSAIRE

Relevance

Structural highlights

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