Wasn't a big part of the reason the Italians established trading posts in the east because there was a lot more trade going on in the east? Remember the Italians were basically the European terminus of the Silk Roads, and a lot of their trade was in goods from much further afield than the Eastern Mediterranean, that was just where they got ahold of them.
Unfortunately, while the Iberian peninsula is rich in natural resources, there's no extremely lucrative luxury goods... Is there anything produced in the Western Mediterranean that could be as profitable? Especially considering that any raw natural resources, etc, must be shipped in huge quantities, whereas the spices and silk and other luxuries from the east were hugely profitable, even if you only had a single ship loaded with them.
It doesn't seem that there's much need for "Spain" (I use the title collectively) as a trading hub until after the discovery of the new world -- which is historically when the balance of lucrative trade switched from the eastern Mediterranean to the western Mediterranean. But the problem is, OTL, by the time the New World was discovered, Castile was already pretty centralized.
So a possible scenario comes to mind wherein the Iberian Peninsula continues to be severely politically disunited. Maybe the Reconquista is much, much less successful (what if the Pope required Spanish knights to join the Crusades in the Holy Land, saying "Jerusalem is more important than Granada!"? Would any of the Spanish knights even go? It seems like the same kind of knights that would go on any crusade, which is to say lord's 2nd and 3rd sons, etc, would join whatever crusade was on regardless of "nationalist" feelings which may not even exist) -- so Columbus's expedition is done in the name of another country. After trade with the new world begins, the Iberian peninsula becomes a sort of "Caribbean in Europe," by which I mean that lots of foreign powers use it as a stopoff place for their trade goods, and their navies. It's the closest part of Europe to the New World, so it's a perfect place to stop off, and it's ruled by all these small little insignificant kingdoms, and the Christians are still squabbling with the Muslims (it also might become sort of like the Balkans if the Christians are unable to get the Muslims out for the foreseeable future) (also the Reformation ITTL, if it even happens, would be something crazy -- no Hapsburg Spain).
So all the major powers (England, France, and also the Italians/Germans to a lesser extent -- what happens to the Netherlands ITTL? Scandinavia? If it's easier for further-east countries to have a neutral stopover point in Spain, will there be more colonizers?) have the local kings make them concessions to use their ports, and over time these "concessions" become more like territories of the "Mother Empire." Whenever the major powers go to war, there is significant proxy fighting in the Spanish mainland as allied kingdoms go to war.
On the whole it would basically be like the rest of Europe colonizing Spain. When allying with Christians, they could use the excuse that they're helping their brothers of the faith against the Muslim threat. When they're allying with the Muslims, they can say that the economic realities of the situation demand allying with Muslims against their fellow Christians.
Anyway, I've got to go, but there's a few ideas, hope they're interesting...