Researchers determine three-dimensional structure of PAPP-A

The three-dimensional structure of PAPP-A has been determined
The laminin G-like (LG) domain of the PAPP-A subunit. Representation to emphasize the separation of the CD (red, cartoon) and the LG domain (magenta, cartoon) by the M domains (transparent surface) in two different orientations. The position of the LG domain in the tetrameric PAPP-A·STC2 structure is shown with the inset above the arrow. Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-33698-8

Danish researchers have determined the three-dimensional structure of the proteolytic enzyme PAPP-A. The results may allow us to better understand the basic biology that regulates linear growth of vertebrates. The same regulatory mechanisms are also involved in several age-related diseases, and thus, the research is an important step towards the development of novel types of drugs.

The growth factor IGF plays a key role in human growth. In the absence of IGF signaling, we become dwarfs. Later in life, IGF is involved in age-related diseases, such as cancer and cardiovascular disease. In both cases, IGF must be converted from an inactive to an active form. This is what PAPP-A is able to do.

"Seven years ago we discovered that the protein STC2 blocks the activity of PAPP-A, thus indirectly inhibiting the activity of the IGF growth factor. To block the activity, STC2 must form a complex with PAPP-A. We have studied this complex, and we now know its ," Professor Claus Oxvig explains.

"It is fascinating to see what a molecule, we know biochemically very well, actually looks like. PAPP-A is heart-shaped with an inner 'chamber'. But from a research point of view, the shape is not the most interesting feature. Rather, it is the interactions between the different elements of the molecule."

The complex between PAPP-A and STC2 is a large molecule, which consists of 3600 amino acids. The catalytic domain of PAPP-A is colored red, and STC2 is colored blue. The active site of the catalytic domain, which includes a bound zinc ion, is shown at a higher magnification. In the movie, the entire complex rotates to emphasize the cavity of the complex . Credit: Claus Oxvig, Aarhus University

There are still many unanswered questions about the , which regulate how much IGF is converted into the active form. It is likely that complex formation between PAPP-A and STC2 is highly regulated. Such a is supported by earlier findings showing that natural human variants of STC2, in which just a is substituted, form the complex with PAPP-A slightly slower. The consequence of this is that slightly more IGF can be activated by PAPP-A, resulting in an increase in height of up to 2.1 cm.

The first-author of the publication reporting the PAPP-A·STC2 structure, graduate student Sara Dam Kobberø, has used cryo- (cryo-EM) to determine the structure of the large protein complex. The Danish National Cryo-EM Research Infrastructure (EMBION, AU) has allowed this study, which has also involved participants from the University of Copenhagen.

The research was published in Nature Communications.

More information: Sara Dam Kobberø et al, Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism, Nature Communications (2022). DOI: 10.1038/s41467-022-33698-8

Journal information: Nature Communications

Provided by Aarhus University

Citation: Researchers determine three-dimensional structure of PAPP-A (2022, October 31) retrieved 2 February 2023 from https://phys.org/news/2022-10-three-dimensional-papp-a.html
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