CSB327 Lecture 9 Summary

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University of Toronto St. George
Cell and Systems Biology
Maurice Ringuette

Lecture 9 Aggrecan - Found in cartilage - Structure o Two N-terminal globular domains  G1  HA binding region (HABR)  LP shares sequence and structural similarity to G1  CD44 is similar to G1  G2  IgG-like o KS chain binding region o CS chain binding region o EGF-like domain o Lectin-like domain o CRP-like domain o One C-terminal globular domain  G3 required for  Transport of aggrecan from ER to Golgi  GAG addition in the Golgi  Secretion from cells - HA-aggrecan aggregate o Aggrecan monomers bind non-covalently to HA chain through LP and G1 dimer  LP increases the binding affinity of aggrecan for HA than G1 alone o Aggrecan monomer is packaged into a small volume of water in cartilage matrix  Creates osmotic pressure o CD44 binds HA-aggrecan aggregate in the pericellular matrix by binding to the core protein of HA o The addition of HA oligosaccharides (HA6) displaces (80% of pericellular membrane)  CD44-bound HA  CD44-bound HA-aggrecan aggregates o The addition of HA oligosaccharides (HA6) cannot displace (20% of pericellular membrane left)  HAS-bound HA  HA-bound aggrecan because of LP o HA oligosaccharides (HA6) can compete for binding with HA - Aggrecan-associated defects o Alizarin red stains bone o Alcian blue stains cartilage o Nanomelia (no G3 domain)  shorter trunk (base of skull to tail) length  autosomal recessive  Lethal chondrodysplasia in chickens  Caused by frame shift mutation creating early stop codon  Only endochondral ossification is affected  Head is not affected because it goes through intramembranous ossification (no cartilage intermediate)  ER quality control  Low aggrecan production  reduction in ECM o Cartilage matrix deficiency (no aggrecan)  autosomal recessive  Lethal chondrodystrophy in mice  Caused by genetic deletion of aggrecan gene  Failure to form the epiphyseal growth plates  Failure to produce aggrecan  very little ECM o Brachymorphism (low sulfation)  Non-lethal growth disorder in mice  Mutation in kinase of PAPS reduces sulfation of GAG chains in aggrec
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