Home Science & Technology Researchers determine the three-dimensional structure of PAPP-A

Researchers determine the three-dimensional structure of PAPP-A

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Nature Communications (2022). DOI: 10.1038/s41467-022-33698-8″ width=”800″ height=”330″/>

The laminin G-like (LG) domain of the PAPP-A subunit. Representation to highlight 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 PAPP-A·STC2 tetrameric structure is indicated by the inset above the arrow. credit: Communications of nature (2022). DOI: 10.1038/s41467-022-33698-8

Danish researchers 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 in vertebrates. The same regulatory mechanisms are also involved in a number of age-related diseases, and thus the research is an important step towards the development of new types of drugs.

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

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

“It’s exciting to see what a molecule that we know very well biochemically actually looks like. PAPP-A is heart-shaped with an internal “chamber”. But from the point of view of the research, the shape is not the most interesting feature.. Rather, it is the interaction between the different elements of the molecule.”

The complex between PAPP-A and STC2 is a large molecule consisting 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 higher magnification. In the film, the entire complex rotates to emphasize the cavity of the complex. Author: Klaus Oxvig, Aarhus University

There are still many unanswered questions about molecular mechanisms, 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 one hypothesis is supported by earlier findings showing that naturally occurring human STC2 variants in which only a one amino acid is replaced, form a complex with PAPP-A somewhat more slowly. The consequence of this is that slightly more IGF can be activated by PAPP-A, leading to an increase in height of up to 2.1 cm.

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

The study was published in Communications of nature.

Additional information:
Sarah Dam Kobberø et al., Structure of the Proteolytic Enzyme PAPP-A with the Endogenous Inhibitor Stanyocalcin-2 Reveals Its Inhibitory Mechanism, Communications of nature (2022). DOI: 10.1038/s41467-022-33698-8

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

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