Insulin-like growth factor-binding protein 7 is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the IGFBP7 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. The major function of the protein is the regulation of availability of insulin-like growth factor

Insulin-like growth factor

The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...

s (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with high affinity. It also stimulates cell adhesion

Cell adhesion

Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...

. The protein is implicated in some cancers.

Interactions

IGFBP7 has been shown to interact

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with Insulin-like growth factor 1

Insulin-like growth factor 1

Insulin-like growth factor 1 also known as somatomedin C is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" in the 1970s.IGF-1 is a hormone similar in molecular...

 and VPS24

VPS24

Charged multivesicular body protein 3 is a protein that in humans is encoded by the VPS24 gene.-Further reading:...

.

RNA Editing

The pre-mRNA of this protein is subject to RNA editing.
The two editing sites were previously recorded as single nucleotide polymorphisms in dbSNP.

Editing type

A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine.Inosines are recognised as guanosine by the cells translational machinery.There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain.ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain.The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence.The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS). It is thought that the pre-mRNA of IGFBP7 is a substrate for ADAR1 based on the expression spectrum of the editing enzyme.

Editing sites

The pre-mRNA of this protein is edited at two positions.These editing sites occur within the insulin growth factor domain.

R/G site

There is an Argine (R) to a Glycine (G) substitution at amino acid position 78 of the final protein.

K/R site

There is a K to R substitiution at amino acid position 95.

The editing complementary sequence (ECS) is located in a region within the coding sequence about 200 base pairs upstream from the editing sites.The ECS forms 140 bp duplex structure.
The A to G discrepancies for these two editing sites were confirmed experimentally to be RNA editing by analyzing matched cDNA and genomic dna sequences from the same tissue sample. Intriguingly, those RNAs that do not need an intron sequence to pair with could, in theory, continue to undergo editing as mature mRNA. A third candidate editing site did not show evidence of RNA editing in sequence analysis, which may be an indication that either the RNA editing process is tissue specific, or editing occurs at a low frequency. One other possible explanation is that these edits are related to specific genomic polymorphisms. The editing site also overlaps with an antisense transcript which could also form a double stranded RNA structure creating a suitable substrate for ADARs.

Editing regulation

Editing is observed in a wide range of tissues. Editing at the R/G site at amino acid position 95 is very high in the human brain.

Structural

The edited sites are found within the insulin growth factor binding domain of IGFBP7 and also Heparin

Heparin

Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

 binding domain.This region is also a site for proteolytic cleavage.Structural analysis of the edited sites determined that the two amino acids that corresponded to the edited sites are not directly involved in binding to IGF-1 but are found in regions flanking them. At position 78 in unedited version of the transcript there is an Arginine close to residue valine-49.This Valine is important in hydrophobic interaction of Phenylalanine of IGF-1.A substitution to a Glycine at this position is thought to introduce additional flexibility leading to a change of loop conformation, thereby disrupting the hydrophobic interaction that stabilises the complex. At amino acid position 98 the unedited transcript contains a lysine .This residue makes some non specific interactions via the aliphatic part of the side chain with Glu-38 of IGF-1.In the edited version the position is an arginine.The long side chain of which is thought to be able to maintain these weak interactions

Function

The edited region contains a proposed heparin binding site and is also part of the recognition sequence for proteolytic cleavage.Heparin binding inhibits cell binding and cell adhesion functions of the protein. Cleavage which occurs at amino acid position 97 reduces heparin binding but modulates the growth stimulatory activity of the protein. Since the editing site occurs within this propsed heparin binding region the effects of editing may have implications for heparin binding and proteolytic clevage and therefore have other affects downstream.Since the protein has been implicated in these processes it is believed editing might effect apoptosis, regulation of cell growth and angiogenesis.. A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7

IGFBP7

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with high...

 signalling promotes the survival of 17–19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis

Neurogenesis

Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

 might be suitable to treat diseases linked to excessive fear memory such as PTSD .