Collagen II containing a Cys substitution for arg-alpha1-519. Homotrimeric monomers containing the mutation do not assemble into fibrils but alter the self-assembly of the normal protein.
ABSTRACT A recombinant system was used to prepare human type II procollagen containing the substitution of Cys for Arg at alpha1-519 found in three unrelated families with early onset generalized osteoarthritis together with features of a mild chondrodysplasia probably best classified as spondyloepiphyseal dysplasia. In contrast to mutated procollagens containing Cys substitutions for obligatory Gly residues, the Cys substitution at alpha1-519 did not generate any intramolecular disulfide bonds. The results were consistent with computer modeling experiments that demonstrated that the alpha carbon distances were shorter with Cys substitutions for obligatory Gly residues than with Cys substitutions in the Y position residues in repeating -Gly-X-Y- sequences of the collagen triple helix. The mutated collagen did not assemble into fibrils under conditions in which the normal monomers polymerized. However, the presence of the mutated monomer in mixtures with normal collagen II increased the lag time for fibril assembly and altered the morphology of the fibrils formed.
- SourceAvailable from: Janna Saarela02/2012; , ISBN: 978-953-51-0063-8
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ABSTRACT: Chondrodysplasias are a group of genetic disorders that affect the development and growth of cartilage. These disorders can result in extreme short stature, craniofacial defects, joint malformation, and early osteoarthritis; severely impacting quality of life for affected individuals. Many chondrodysplasias are caused by mutations in genes encoding cartilage extracellular matrix (ECM) proteins. These mutations typically result in synthesis of abnormal proteins that are improperly folded, and hence inappropriately retained within the endoplasmic reticulum (ER) of the cell, activating ER stress and the Unfolded Protein Response (UPR), an adaptive cellular response to minimize production of the mutant protein and/or to enhance protein folding, degradation or export. If prolonged, activation of the UPR causes apoptotic cell death. Many human disorders have an underlying mechanism in UPR activation, and targeting ER stress pathways is showing promise for development of therapeutics for these conditions. Understanding and modeling the UPR in chondrodysplasia will be essential to advance such targeted approaches for the benefit of chondrodysplasia patients. The focus of this review is to compare the mechanistic sequelae of ECM protein mutations in chondrodysplasia that may cause chondrocyte ER stress and UPR activation, and to present current and future directions in chondrodysplasia disease modeling and therapeutic intervention. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc.Developmental Dynamics 03/2014; · 2.59 Impact Factor
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ABSTRACT: Collagens form critical elements of extracellular matrices that provide mechanical strength to skeletal tissues and serve as a binding platform for cells of bone and cartilage. The formation of collagen-rich extracellular matrices is a complex process that involves intracellular and extracellular steps. Mutations in genes that encode individual chains of triple-helical collagens present in bone and cartilage are associated with heritable diseases of skeletal tissues. In addition, mutations in genes encoding proteins involved in the intracellular and extracellular modifications of collagens are also responsible for developing skeletal abnormalities. In this review, we will summarize the pathomechanisms of molecular and cellular consequences of mutations that alter collagen structure and function. Moreover, we will discuss the prospects and limitations of therapeutic approaches to minimize the effects of mutations that affect collagens of skeletal tissues.The international journal of biochemistry & cell biology 05/2013; · 4.89 Impact Factor