Pro‐forms of growth factors have received increasing attention since it was shown that they can affect both the maturation and functions of mature growth factors. Here, we assessed the biological function of the pro‐form of bone morphogenetic protein‐2 (BMP‐2), a member of the transforming growth factor β (TGFβ)/ΒΜP superfamily. The role of the 263 amino acids of the pro‐peptide is currently unclear. In order to obtain an insight into the function of the pro‐form (proBMP‐2), the ability of proBMP‐2 to induce alkaline phosphatase (AP), a marker enzyme for cells differentiating into osteoblasts, was tested. Interestingly, in contrast to mature BMP‐2, proBMP‐2 did not lead to induction of AP. Instead, proBMP‐2 inhibited the induction of AP by BMP‐2. This result raised the question of whether proBMP‐2 may compete with mature BMP‐2 for receptor binding. ProBMP‐2 was found to bind to the purified extracellular ligand binding domain (ECD) of BMPR‐IA, a high‐affinity receptor for mature BMP‐2, with a similar affinity as mature BMP‐2. Binding of proBMP‐2 to BMPR‐IA was confirmed in cell culture by cross‐linking proBMP‐2 to BMPR‐IA presented on the cell surface. In contrast to this finding, proBMP‐2 did not bind to the ECD of BMPR‐II. ProBMP‐2 also differed from BMP‐2 in its capacity to induce p38 and Smad phosphorylation. The data presented here suggest that the pro‐domain of BMP‐2 can alter the signalling properties of the growth factor by modulating the ability of the mature part to interact with the receptors. Structured digital abstract  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261817:BMPR‐IA (uniprotkb:http://www.ebi.uniprot.org/entry/P36894) and proBMP2 (uniprotkb:http://www.ebi.uniprot.org/entry/P12643) physically interact (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915) by cross‐linking studies (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0030)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261681, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261693: BMP2 (uniprotkb:http://www.ebi.uniprot.org/entry/P12643) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to BMPR‐IA (uniprotkb:http://www.ebi.uniprot.org/entry/P36894) by enzyme linked immunosorbent assay (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0411)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261751, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261794: proBMP2 (uniprotkb:http://www.ebi.uniprot.org/entry/P12643) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to BMPR‐IA (uniprotkb:http://www.ebi.uniprot.org/entry/P36894) by competition binding (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0405)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261806, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7261846: BMPR‐IA (uniprotkb:http://www.ebi.uniprot.org/entry/P36894) physically interacts (http://www.ebi.ac.uk/ontology...

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Histological mitochondrial changes are generally found to be associated with late onset myofibrillar myopathies (MFMs). How these changes contribute to the pathogenesis of MFMs is unknown. Mitochondrial changes, including COX-deficient fibers (n = 8), biochemical activities of respiratory chain complexes (n = 7), and multiple mtDNA deletions by long-range PCR (n = 9) were examined in patients with genetically confirmed MFMs [MYOT (n = 2), DES (n = 1), ZASP (n = 2), FLNC (n = 4)] and compared with age and sex matched normal controls (n = 27) and patients with a mitochondrial disorder with multiple mtDNA deletions due to nuclear genetic defects (n = 8). In 2 MFM patients, micro dissected fibers were analyzed for multiple mtDNA deletions by nested long-range PCR. The COX-deficient fibers only partly corresponded with fibers containing myofibrillar accumulations. In total, there was no difference in the percentage of COX-deficient fibers in MFM patients and normal controls. However, the percentage of COX-deficient fibers was significantly higher in 3 MFM patients. Two MFM patients but none of the controls had multiple mtDNA deletions. Nested long-range PCR detected multiple mtDNA deletions only in COX-deficient fibers. Citrate synthase activities in MFM patients were 1.5-fold increased by compared to those in controls, suggesting initiation of mitochondrial alterations. However, it is unclear whether this is a direct consequence of MFM pathology. *both authors contributed equally to the manuscript.

We have previously shown that the pro-peptide of human nerve growth factor (NGF) facilitates oxidative folding of the mature part. For the analysis of functional specificities of the pro-peptides of NGF and the related neurotrophin-3 (NT-3) with respect to structure formation, chimeric proteins with swapped pro-peptides were generated. Neither the structure nor the stability of the mature domains was influenced by the heterologous pro-peptides. For the pro-peptide of NT-3 fused to the mature part of NGF, stabilization of the pro-peptide moiety by the NGF part was observed. Folding kinetics and renaturation yields of this chimeric protein were comparable to those of proNGF. Our results demonstrate functional interchangeability between the pro-peptides of NGF and NT-3 with respect to their role in assisting oxidative folding of the mature part.