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The polyubiquitinated substrate is degraded by a multicatalytic complex based on

a 20S proteasome (the S stands for Svedberg, see Section 3.5.3). Proteasomes are

multisubunit proteases with a cylindrical core that has a ‘lid’ at both ends. The

catalytic sites are within the core cylinder. The 20S proteasome consists of 14

a-subunits and 14b-subunits arranged in four rings each of seven units. The proteo-

lytic activity is located in theb-subunits at five sites that lie in the core. Entry of the

substrate protein into the cylindrical core is controlled by a number of activators and

Ub

Hul5 Ubp6

Ub

ATP

ADP ATP

ADP

ATP

ADP

Ubp6

Substrate

engagement

Unfolding and

translocation

Rpn11

(Ub)n

Proteasome degradation cycle

Binding

Substrate (Ub)n-substrate

DeUbs

E1, E2, E3

Proteolysis

Peptide

release

Regulatory

particle

Core particle

Fig. 15.16Proteasome-degrading cycle, incorporating Hul5 and Ubp6 activities. Substrates are

polyubiquitinated through the action of E1, E2 and E3 enzymes. Following binding to the proteasome,

substrates are either engaged, unfolded and degraded in an ATP-dependent manner, with concomitant removal

of the polyubiquitin chain by Rpn11, or are released from the proteasome. Release can be accelerated through

the deubiquitinating action of Ubp6, which decreases substrate affinity. Further elongation of the ubiquitin

chain by Hul5 increases affinity of the substrate for the proteasome, decreasing the release rate and thereby

increasing degradation. The balance of Ubp6 and Hul5 activities can therefore affect the partitioning between

binding and release by modifying the polyubiquitin chain length and thereby affecting the release rate.

(Reproduced from D. A. Kraut, S. Prakash and A. Matouschek (2007). To degrade or release: ubiquitin-chain

remodelling.Trends in Cell Biology, 17 , 419–421, by permission of Elsevier Science.)

623 15.5 Control of enzyme activity