The three-dimensional solution structure of the complex between calcium-bound calmodulin (Ca(2+)-CaM) and a 26-residue synthetic peptide comprising the CaM binding domain (residues 577 to 602) of skeletal muscle myosin light chain kinase, has been determined using multidimensional heteronuclear filtered and separated nuclear magnetic resonance spectroscopy. The two domains of CaM (residues 6 to 73 and 83 to 146) remain essentially unchanged upon complexation. The long central helix (residues 65 to 93), however, which connects the two domains in the crystal structure of Ca(2+)-CaM, is disrupted into two helices connected by a long flexible loop (residues 74 to 82), thereby enabling the two domains to clamp residues 3 to 21 of the bound peptide, which adopt a helical conformation. The overall structure of the complex is globular, approximating an ellipsoid of dimensions 47 by 32 by 30 angstroms. The helical peptide is located in a hydrophobic channel that passes through the center of the ellipsoid at an angle of approximately 45 degrees with its long axis. The complex is mainly stabilized by hydrophobic interactions which, from the CaM side, involve an unusually large number of methionines. Key residues of the peptide are Trp4 and Phe17, which serve to anchor the amino- and carboxyl-terminal halves of the peptide to the carboxyl- and amino-terminal domains of CaM, respectively. Sequence comparisons indicate that a number of peptides that bind CaM with high affinity share this common feature containing either aromatic residues or long-chain hydrophobic ones separated by a stretch of 12 residues, suggesting that they interact with CaM in a similar manner.

https://science.sciencemag.org/content/sci/256/5057/632.full.pdf

Solution structure of a calmodulin-target peptide complex by multidimensional NMR.

There is an unmet medical need for anabolic treatments to restore lost bone Human genetic bone disorders provide insight into bone regulatory processes Sclerosteosis is a disease typified by high bone mass due to the loss of SOST expression Sclerostin, the SOST gene protein product, competed with the type I and type II bone morphogenetic protein (BMP) receptors for binding to BMPs, decreased BMP signaling and suppressed mineralization of osteoblastic cells SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts Strong expression in osteocytes suggested that sclerostin expressed by these central regulatory cells mediates bone homeostasis Transgenic mice overexpressing SOST exhibited low bone mass and decreased bone strength as the result of a significant reduction in osteoblast activity and subsequently, bone formation Modulation of this osteocyte-derived negative signal is therapeutically relevant for disorders associated with bone loss

/pdf/osteocyte-control-of-bone-formation-via-sclerostin-a-novel-4hqt3q55ag.pdf

Osteocyte control of bone formation via sclerostin, a novel BMP antagonist.

Structural organization, ion transport, and energy transduction of p-type atpases

Ca2+-ATPases (pumps) are key actors in the regulation of Ca2+ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery They have high affinity for Ca2+ and can efficiently regulate it down to very low concentration levels Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+ The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca2+ homeostasis that are incompatible with cell life However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca2+-controlling and/or processing machinery They do not bring cells to immediate death but seriously compromise their normal functioning

Calcium Pumps in Health and Disease

Calcium pumps of the plasma membrane (also known as plasma membrane Ca2+-ATPases or PMCAs) are responsible for the expulsion of Ca2+ from the cytosol of all eukaryotic cells. Together with Na+/Ca2+ exchangers, they are the major plasma membrane transport system responsible for the long-term regulation of the resting intracellular Ca2+concentration. Like the Ca2+ pumps of the sarco/endoplasmic reticulum (SERCAs), which pump Ca2+ from the cytosol into the endoplasmic reticulum, the PMCAs belong to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. Mammalian PMCAs are encoded by four separate genes, and additional isoform variants are generated via alternative RNA splicing of the primary gene transcripts. The expression of different PMCA isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological need...

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.1.21

Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps.

Complete primary structure of a human plasma membrane Ca2+ pump.

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Complete primary structure of a human plasma membrane Ca2+ pump.